Natural Extracts Abolished Lipid Accumulation in Cells Harbouring non-favourable PNPLA3 genotype

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"documento" => "article" "crossmark" => 0 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "Ann Hepatol. 2018;17:250-5" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 148 "formatos" => array:3 [ "EPUB" => 10 "HTML" => 101 "PDF" => 37 ] ] "en" => array:11 [ "idiomaDefecto" => true "titulo" => "More Evidence for the Genetic Susceptibility of Mexican Population to Nonalcoholic Fatty Liver Disease through PNPLA3" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "250" "paginaFinal" => "255" ] ] "contieneResumen" => array:1 [ "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "f0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 406 "Ancho" => 664 "Tamanyo" => 38933 ] ] "descripcion" => array:1 [ "en" => "Hypothesized Mexican network showing interaction between the PNPLA3, LYPLAL1 and GCKR. All of them were involved in NAFLD development. The lines represent transcriptional regulation between genes. PNPLA3 gene is located in chromosome 22 and encodes a protein closely related to triglyceride lipase, the main TAG hydrolase in adipose tissue. The 148 M mutation determines a critical aminoacid substitution near the catalytic domain, decreasing the access substrates and PNPLA3 enzimatic activity towards lipids. Additionally, the genetic variant of GCKR, rs780094, reduces the ability to inhibit glucokinase in response of fructose-6-phosphate. It is important to recall that this gene is a glucokinase regulator, thereby, its inhibition results in insulin resistance. Finally, LYPLAL1 has demonstrated a role in consecutive steps of triglyceride breakdown. The combined effects of thes e polyphomisms have been proposed to explain an important role of NAFLD development. LYPLAL1: Lysophospholipase like 1. PNPLA3: patatin-like phospholipase domain containing 3. GCKR: Glucokinase regulatory protein. TAG: Triacylglycerol. FFAs: Free Fatty Acids. NAFLD: Nonalcoholic Fatty Liver Disease." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Paulina Chinchilla-López, Oscar Ramírez-Pérez, Vania Cruz-Ramón, Samuel Canizales-Quinteros, Aarón Domínguez-López, Guadalupe Ponciano-Rodríguez, Fausto Sánchez-Muñoz, Nahum Méndez-Sánchez" "autores" => array:8 [ 0 => array:2 [ "nombre" => "Paulina" "apellidos" => "Chinchilla-López" ] 1 => array:2 [ "nombre" => "Oscar" "apellidos" => "Ramírez-Pérez" ] 2 => array:2 [ "nombre" => "Vania" "apellidos" => "Cruz-Ramón" ] 3 => array:2 [ "nombre" => "Samuel" "apellidos" => "Canizales-Quinteros" ] 4 => array:2 [ "nombre" => "Aarón" "apellidos" => "Domínguez-López" ] 5 => array:2 [ "nombre" => "Guadalupe" "apellidos" => "Ponciano-Rodríguez" ] 6 => array:2 [ "nombre" => "Fausto" "apellidos" => "Sánchez-Muñoz" ] 7 => array:2 [ "nombre" => "Nahum" "apellidos" => "Méndez-Sánchez" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1665268119301577?idApp=UINPBA00004N" "url" => "/16652681/0000001700000002/v1_201905140709/S1665268119301577/v1_201905140709/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S1665268119301553" "issn" => "16652681" "doi" => "10.5604/01.3001.0010.8640" "estado" => "S300" "fechaPublicacion" => "2018-03-01" "aid" => "70032" "copyright" => "Fundación Clínica Médica Sur, A.C." "documento" => "article" "crossmark" => 0 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "Ann Hepatol. 2018;17:232-41" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 159 "formatos" => array:3 [ "EPUB" => 10 "HTML" => 95 "PDF" => 54 ] ] "en" => array:11 [ "idiomaDefecto" => true "titulo" => "Long-Term Follow-up and Quantitative Hepatitis B Surface Antigen Monitoring in North American Chronic HBV Carriers" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "232" "paginaFinal" => "241" ] ] "contieneResumen" => array:1 [ "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "f0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 382 "Ancho" => 500 "Tamanyo" => 16321 ] ] "descripcion" => array:1 [ "en" => "Comparison of qHBsAg levels by disease phase among treatment naïve patients with chronic hepatitis B. qHBsAg: quantitative hepatitis b surface antigen. HBeAg: hepatitis B e antigen. CHB: chronic hepatitis B." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Conar R. O’Neil, Stephen E. Congly, M. Sarah Rose, Samuel S. Lee, Meredith A. Borman, Carmen L. Charlton, Carla Osiowy, Mark G. Swain, Kelly W. Burak, Carla S. Coffin" "autores" => array:10 [ 0 => array:2 [ "nombre" => "Conar R." "apellidos" => "O’Neil" ] 1 => array:2 [ "nombre" => "Stephen E." "apellidos" => "Congly" ] 2 => array:2 [ "nombre" => "M. Sarah" "apellidos" => "Rose" ] 3 => array:2 [ "nombre" => "Samuel S." "apellidos" => "Lee" ] 4 => array:2 [ "nombre" => "Meredith A." "apellidos" => "Borman" ] 5 => array:2 [ "nombre" => "Carmen L." "apellidos" => "Charlton" ] 6 => array:2 [ "nombre" => "Carla" "apellidos" => "Osiowy" ] 7 => array:2 [ "nombre" => "Mark G." "apellidos" => "Swain" ] 8 => array:2 [ "nombre" => "Kelly W." "apellidos" => "Burak" ] 9 => array:2 [ "nombre" => "Carla S." "apellidos" => "Coffin" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1665268119301553?idApp=UINPBA00004N" "url" => "/16652681/0000001700000002/v1_201905140709/S1665268119301553/v1_201905140709/en/main.assets" ] "en" => array:17 [ "idiomaDefecto" => true "titulo" => "Natural Extracts Abolished Lipid Accumulation in Cells Harbouring non-favourable PNPLA3 genotype" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "242" "paginaFinal" => "249" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Ángela Rojas, Paloma Gallego, Antonio Gil-Gómez, Rocío Muñoz-Hernández, Lourdes Rojas, Rosario Maldonado, Rocío Gallego-Durán, Marta García-Valdecasas, José A. Del Campo, Juan D. Bautista, Manuel Romero-Gómez" "autores" => array:11 [ 0 => array:3 [ "nombre" => "Ángela" "apellidos" => "Rojas" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "aff0005" ] ] ] 1 => array:3 [ "nombre" => "Paloma" "apellidos" => "Gallego" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "**" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "Antonio" "apellidos" => "Gil-Gómez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "aff0005" ] ] ] 3 => array:3 [ "nombre" => "Rocío" "apellidos" => "Muñoz-Hernández" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "aff0005" ] ] ] 4 => array:3 [ "nombre" => "Lourdes" "apellidos" => "Rojas" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "aff0005" ] ] ] 5 => array:3 [ "nombre" => "Rosario" "apellidos" => "Maldonado" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "***" "identificador" => "aff0015" ] ] ] 6 => array:3 [ "nombre" => "Rocío" "apellidos" => "Gallego-Durán" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "aff0005" ] ] ] 7 => array:3 [ "nombre" => "Marta" "apellidos" => "García-Valdecasas" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "aff0005" ] ] ] 8 => array:3 [ "nombre" => "José A. Del" "apellidos" => "Campo" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "**" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "****" "identificador" => "aff0020" ] ] ] 9 => array:3 [ "nombre" => "Juan D." "apellidos" => "Bautista" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "****" "identificador" => "aff0020" ] ] ] 10 => array:4 [ "nombre" => "Manuel" "apellidos" => "Romero-Gómez" "email" => array:1 [ 0 => "mromerogomez@us.es" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Laboratorio de Investigación clínica y traslacional en enfermedades hepáticas y digestivas y CIBERehd. Instituto de Biomedicina de Sevilla (IBiS). Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain" "etiqueta" => "*" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "UGC de enfermedades hepáticas y digestivas, CIBERehd. Hospital Universitario de Valme, Sevilla, Spain" "etiqueta" => "**" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Unidad de Farmacología Clínica y Experimental. Hospital Universitario de Valme, Seville, Spain" "etiqueta" => "***" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, Seville, Spain" "etiqueta" => "****" "identificador" => "aff0020" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "*" "correspondencia" => "Corresponding author." ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "f0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 231 "Ancho" => 320 "Tamanyo" => 10750 ] ] "descripcion" => array:1 [ "en" => "Possible mechanisms about the beneficial effects of quercetin and aqueous extracts in NAFLD." ] ] ] "textoCompleto" => "IntroductionNon-alcoholic fatty liver disease (NAFLD) is defined as the accumulation of excessive fat in the liver in the absence of excessive drinking of alcohol.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> It has been included as a metabolic abnormality such as obesity, type 2 diabetes, arterial hypertension, and hypertriglyceridemia.<a class="elsevierStyleCrossRef" href="#bib0010">2</a>,<a class="elsevierStyleCrossRef" href="#bib0015">3</a> NAFLD encompasses a wide spectrum of liver damage ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), advanced fibrosis, and rarely, progression to cirrhosis and hepatocellular carcinoma.<a class="elsevierStyleCrossRef" href="#bib0020">4</a>Hepatic steatosis can either be a benign, non-inflammatory condition, or can be associated with non-alcoholic steatohepatitis (NASH). The earliest stage is characterized by the excessive triglycerides (TGs) accumulation as lipid droplets (LDs) in the cytoplasm of hepatocytes. Hepatic steatosis is often self-limited, however it can progress to NASH, which is known by the presence of hepatocyte injury (hepatocyte ballooning and cell death), inflammatory infiltrate, and/or collagen deposition (fibrosis).<a class="elsevierStyleCrossRef" href="#bib0025">5</a> It has been postulated that the inhibition of excessive lipid synthesis and uptake could be an effective intervention for NASH.<a class="elsevierStyleCrossRef" href="#bib0030">6</a>,<a class="elsevierStyleCrossRef" href="#bib0035">7</a>Dietary fat is one of the most important environmental factors associated with the incidence of NAFLD. The search of functional food ingredients such as herbal extracts or flavonoids capable to suppress the accumulation of hepatic lipid<a class="elsevierStyleCrossRefs" href="#bib0040">8</a>–<a class="elsevierStyleCrossRef" href="#bib0060">12</a> by the modulation of several pathways is ongoing. Several polyphenols and phenolic compounds, such anthocyanins, curcumin, resveratrol, silymarin and those present in coffee and tea have been proposed as NAFLD treatment but the varying bioavailability remains poor, so further studies are needed for the future clinical applications.<a class="elsevierStyleCrossRef" href="#bib0065">13</a>Steatosis could be modulated by genetic susceptibility.<a class="elsevierStyleCrossRef" href="#bib0070">14</a> In 2008, Romeo, et al. performed an independent genome-wide association study to identify genetic determinants of liver steatosis.<a class="elsevierStyleCrossRef" href="#bib0075">15</a> The author figured out that the polymorphism rs738409 C>G in PNPLA3 gene was robustly associated with an increased risk for hepatic steatosis. Patatin-like phospholipase domain-containing protein 3 (PNPLA3) is a transmembrane protein expressed prominently in hepatocytes and the substitution I148M has been suggested to impair TG hydrolysis in hepatocytes, favouring its accumulation.<a class="elsevierStyleCrossRef" href="#bib0080">16</a> Recently it has been proposed that PNPLA3-148M evade ubiquitylation and proteasomal degradation, resulting in the accumulation of PNPLA3-148M on the surfaces of lipid droplets impairing TGs mobilization from LDs.<a class="elsevierStyleCrossRef" href="#bib0085">17</a> The discovery of new drugs to reduce the risk of NAFLD would be useful considering the genetics factors. The purposes of this study were to elucidate the role of quercetin and other water-soluble extracts in an in-vitro model with unfavourable genotype GG for PNPLA3.<a class="elsevierStyleCrossRef" href="#bib0090">18</a>Material and MethodsCell CultureHuh7.5 cells were routinely cultured in DMEM (ThermoFisher, MA, USA) supplemented with 10% FBS and 1% penicillin-streptomycin in an incubator under an atmosphere of 5% CO2 at 37 °C. The Huh7.5 cell model of OA-induced intracellular lipid accumulation was developed as previously described.<a class="elsevierStyleCrossRef" href="#bib0095">19</a> Cells were cultured with 1mM of Oleic acid for 48 h. Control cells were treated with FFA-free medium containing the vehicle dimethyl sulfoxide (DMSO).PNPLA3 genotypingDNA from cells was extracted using the DNA isolation Kit with the MagNA Pure LC Instruments (Roche). The rs738409 SNPs were analysed using the StepOnePlus Real Time PCR System (Applied Biosystem, Foster City, USA) with a Taqman SNP Genotyping Assay, using published sequences from the NCBI Entrez SNP Database (<a href="http://www.ncbi.nlm.nih.gov/sites/entrez">www.ncbi.nlm.nih.gov/sites/entrez</a>) (rs738409: 5’-AAG-GAGGGATAAGGCCACTGTA-3 as forward and 5’-CTTTCACAGGCCTTGGTATGTTC-3’ as reverse primer).Preparation of aqueous extractsWhite button mushrooms (Agaricus bisporus) were used as raw material after cultivation in a pilot plant at the University of Seville (Spain), according to standard procedures. All chemicals used were of analytical grade. Agaricus bisporus Aqueous Extract (AbAE) was obtained by an enzymatic procedure based on the protocol described by Cremades and colleagues.<a class="elsevierStyleCrossRef" href="#bib0100">20</a> Briefly, after A. bisporus homogenization (10g + 10 mL distilled water) and enzymatic digestion with a mixture of glucanase and chitinase enzymes (Novo Nordisk®, Denmark) at pH = 5, temperature 55 °C and an enzyme/substrate ratio of 0.01, for 24 h. Finally, temperature was raised up to 90 °C for 120 min to inactivate the enzymes. After cooling to room temperature, pH was adjusted to 7.0 with 1M NaOH and centrifuged at 8000 × g. The supernatant was collected and filtered through a 0.2 µm membrane, using the filtrate as “crude AbAE” for activity assays. Cynara scolymus aqueous extracts were obtained by a similar procedure but using a mixture of celluloses and proteases as hydrolytic agent.<a class="elsevierStyleCrossRef" href="#bib0100">20</a>Detection of LDs by Fluorescent Microscopy Oil Red O (ORO) cell staining.Neutral lipids stored into the LDs were visualized by fluorescence microscopy using ORO staining (SigmaAldrich, MO, USA), a vital lipophilic dye used to label fat accumulation in the cytosol, according to Hu and colleagues.<a class="elsevierStyleCrossRef" href="#bib0105">21</a> To analyze fat accumulation 20,000 Huh7.5 cells were seeded and grown on coverslips in 24 wells plate. Huh7.5 cells were cultured in the presence of oleic acid 1mM diluted in DMSO (less than 0.01% of total volume) and treated for 48h with 50 µM of quercetin (HWI ANALYTIK, GmbH, Germany) or 0.1 mg/mL of water-soluble extract from A. Bisporus (M) or Cynara scolymus (A). The cells were rinsed two times with phosphate-buffered saline (PBS) pH 7.4, fixed with 4% paraformaldehyde in PBS for 10min and permeabilised with 0.2% Triton X-100 for 2 min. Nuclei cells were stained with 46-diamidino- 2phenylindole (DAPI) for 30min at room temperature, and neutral lipids were stained with ORO as previously described.<a class="elsevierStyleCrossRef" href="#bib0110">22</a> Images were acquired with a fluorescence microscope (OLYMPUS BX41) equipped with the standard epifluorescence filter set up for DAPI and FITC. For determination of LD diameter images were captured under oil with a 100x plan apochromat objective. Analyses were performed on three independent experiments measuring at least 100 cells for each treatment using Imaging Software cell^F (Olympus, Tokyo, Japan).Fluorimetric determination of intracellular fat content - Nile red stainingThe intracellular fat content was determined fluorimetrically based on Nile Red staining, a vital lipophilic dye used to label fat accumulation in the cytosol.<a class="elsevierStyleCrossRef" href="#bib0115">23</a> Ten thousand Huh7.5 cells were grown in 96 plate wells, exposed to oleic acid and treated with quercetin and water-soluble M or A for 48 h. AdipoRed™ Reagent (Lonza, Basel, Switzerland) was added to each well and incubated at room temperature for 10 min. Intensity fluorescence was quantified using Synergy HT at 485/572 nm (BioTeK, VT, USA) and normalized to protein concentration.RNA isolation, retro-transcription and quantitative polymerase chain reaction (q-PCR)Total RNA was extracted from the above-treated cells using the guanidine isothiocyanate method.<a class="elsevierStyleCrossRef" href="#bib0120">24</a> RNA samples were treated with DNaseI. Total RNA was subjected to reverse transcription (RT) using commercially available kits (QuantiTect Rev. Transcription Kit; Qiagen, Hilden, Germany) according to the manufacturer’s instructions. SREBP-lc, PPARγ, PPARα, ACAT, DGAT-1, DGAT-2, FASN, MTTP, APOB and APOE gene expression levels were analysed using commercial oligonucleotides (Qiagen, Hilden, Germany).Statistical AnalysisContinuous variables are described as means ± SD of minimum three independent experiments. The Student t-test was used for comparisons between groups. P values P < 0.05 (*) p < 0.01 (**) and p < 0.001 (***) were considered statistically significant.ResultsHuh7.5 PNPLA3 genotypeHuh7.5 cells presented unfavourable genotype GG for PNPLA3 as previously was showed.<a class="elsevierStyleCrossRef" href="#bib0090">18</a>Oleic acid-induced intracellular lipid accumulation in Huh7.5 cellsUsing oil red staining we observed that untreated Huh7.5 cells revealed almost absence of intracellular lipid (<a class="elsevierStyleCrossRef" href="#f0005">Figure 1</a>A). However, as shown in <a class="elsevierStyleCrossRef" href="#f0005">figure 1</a>B, after OA exposure LD were higher in number and size.<elsevierMultimedia ident="f0005"></elsevierMultimedia>Using a fluorescence-based AdipoRedTM assay, the amount of intracellular lipids increased in the presence of OA 78.31 ± 3.78% compared to untreated cells (<a class="elsevierStyleCrossRef" href="#f0005">Figure 1</a>С).Effects of Quercetin and water-soluble extracts from mushroom and artichoke on hepatic lipid accumulationFirst, we have determined the dose by cytotoxic assay and at 0.1 mg/mL no toxic effects were observed (data not shown). A significant reduction in lipid accumulation was observed by microscopy after quercetin or extracts addition (<a class="elsevierStyleCrossRef" href="#f0010">Figure 2</a>A). After treatment, a significant reduction of the LD size in OA-treated cells was found (<a class="elsevierStyleCrossRef" href="#f0010">Figure 2</a>B). Intracellular lipid concentration was decreased in OA-treated cells by quercetin (66 ± 2.04%), M aqueous extract (20.40 ± 3.63%) and A aqueous extract (24.61± 0.19%) (<a class="elsevierStyleCrossRef" href="#f0010">Figure 2</a>C).<elsevierMultimedia ident="f0010"></elsevierMultimedia>Aqueous extracts modulated lipogenesis-related gene expressionGenes involved in lipogenesis (SREBP-1c, PPARγ and PPARα), significantly increased in OA-induced Huh7.5 cells at the mRNA levels (p < 0.05) (<a class="elsevierStyleCrossRef" href="#f0015">Figure 3</a>). As shown in <a class="elsevierStyleCrossRef" href="#f0015">figure 3</a>A, quercetin treatment decreased the expression of SREBP-1c (fold inhibition: 1.57 ± 0.13) and PPARy (fold inhibition: 0.77 ± 0.10). The same effect was observed after treatment with the aqueous-extracts. Conversely, quercetin and artichoke extract increased the gene expression of PPARα (<a class="elsevierStyleCrossRef" href="#f0015">Figure 3</a>A). ACAT gene expression was increased by OA 1mM and decreased significantly (fold inhibition: 1.48 ± 0.3) after quercetin treatment being this reduction less significantly after extract addition (<a class="elsevierStyleCrossRef" href="#f0015">Figure 3</a>B). Genes implicated on triglycerides and VLDL pathways were also modulated in OA-induced Huh7.5 cells. DGAT-l and APOE mRNA levels were significantly increased and MTTP and APOB were decreased in OA-induced Huh7.5 cells (p > 0.05). Quercetin and artichoke extract decreased DGAT1 mRNA levels in Huh7.5 and the apolipoproteins genes were repressed by quercetin in the OA-induced model (<a class="elsevierStyleCrossRef" href="#f0005">Figure 1</a>D).<elsevierMultimedia ident="f0015"></elsevierMultimedia>DiscussionCurrent NAFLD therapies include lifestyle modifications, physical activity and medical intervention. Probiotics, functional food and several natural compounds (i.e. resveratrol and quercetin,<a class="elsevierStyleCrossRef" href="#bib0125">25</a> anthocyanins,<a class="elsevierStyleCrossRef" href="#bib0130">26</a> vitamin E<a class="elsevierStyleCrossRef" href="#bib0135">27</a>) may be promising in helping therapeutic approaches. On the basis of these data, it seems that foods rich in quercetin and/or including natural extracts from mushroom and artichoke may be useful for the prevention of NAFLD.In addition to resveratrol and quercetin, other polyphenols such as Anthocyanin Cy-3-g, Proanthocyanidins, Theaflavin (a flavan-3-ol) and Ellagic acid have been studied as potential agent for both prevention and treatment of hepatic steatosis.<a class="elsevierStyleCrossRefs" href="#bib0140">28</a>–<a class="elsevierStyleCrossRef" href="#bib0155">31</a> Resveratrol is a stilbene occurring naturally in several plants and provided in the diet by various foodstuffs. In recent years, it has been shown to modify lipid metabolism, and more specifically to induce a reduction in liver triacylglycerol content.<a class="elsevierStyleCrossRefs" href="#bib0160">32</a>–<a class="elsevierStyleCrossRef" href="#bib0170">34</a>Quercetin is a natural polyphenol belonging to a group with a variable structure, known as flavonoids. It is found in onions, broccoli, tomatoes, apples and berries. Several studies have shown that quercetin has more than one effect in order to modify the intracellular lipid content.<a class="elsevierStyleCrossRef" href="#bib0055">11</a> Vidyashankar and colleagues<a class="elsevierStyleCrossRef" href="#bib0175">35</a> showed that quercetin decreased triacylglycerol accumulation, modulated the insulin resistance, inflammatory cytokine secretion, and increased cellular antioxidants suggesting that quercetin could be an effective molecule for NAFLD.In this study, we have shown that aqueous extracts from mushroom and artichoke may be useful for therapeutic interventions in lipid accumulation-related liver pathologies like NAFLD. Beneficial effects of polyphenols in the prevention and treatment of liver steatosis have been widely reported.<a class="elsevierStyleCrossRef" href="#bib0125">25</a>,<a class="elsevierStyleCrossRef" href="#bib0180">36</a> These molecules present hepaticprotective effects because they reduce liver fat accumulation, mainly by lowering lipogenesis and increasing fatty acid oxidation. Besides, it has been shown that polyphenols are able to reduce oxidative stress and inflammation, the main factors responsible for liver damage.<a class="elsevierStyleCrossRef" href="#bib0185">37</a> To date, these beneficial effects have been demonstrated in cultured cells and animal models.Quercetin was used as a reference or like a positive control.<a class="elsevierStyleCrossRef" href="#bib0055">11</a> Our results confirm that quercetin reduces TGs concentration and LDs size in an OA in vitro model. The use of aqueous extracts showed similar effects than quercetin such as an important reduction of intracellular lipid content, LD size and intracellular triglycerides concentration.Lipid accumulation in the liver may be caused by enhanced de novo lipogenesis, activation of lipid uptake, and lowering of lipid catabolism. Fatty acids are known to be ligands for nuclear transcription factors, such as SREBP-1c, PPARγ and PPARα.<a class="elsevierStyleCrossRef" href="#bib0190">38</a> It has been reported that PPARα knockout (-/-) mice developed severe hepatic steatosis upon fasting as a result of failure to up-regulate the fatty acid oxidation pathway.<a class="elsevierStyleCrossRef" href="#bib0195">39</a>PPARα activation is required to enhance hepatic lipid turnover to enable sufficient clearance of lipids from the liver, preventing lipid accumulation and peroxidation in murine NASH models.<a class="elsevierStyleCrossRef" href="#bib0200">40</a> Our result confirmed that the therapeutic effect of quercetin on lipid metabolism in Huh7.5-induced fatty liver cells is partly due to PPARα upregulation (inducing lipolysis) and SREBP-1c downregulation (reducing lipogenesis).<a class="elsevierStyleCrossRef" href="#bib0205">41</a>,<a class="elsevierStyleCrossRef" href="#bib0210">42</a>Cynara scolymus extract increased PPARα gene expression levels in the model of steatosis which controls fatty acid degradation. Anderson, et al. showed that pathogenesis of NASH increased the pool of free fatty acids through de novo lipid synthesis and nuclear receptors activation (SREBP-1, ChREBP-1, and PPARγ).<a class="elsevierStyleCrossRef" href="#bib0215">43</a> In our study, OA significantly increased SREPB-lc gene expression which was disrupted by quercetin. In addition, PPARγ gene expression was induced by OA and this effect was diminished after treatment. Beside, we demonstrated that OA modified genes involved in TGs synthesis and VLDL secretion pathway however quercetin and aqueous extracts treatment did not affect on their expression. This work demonstrated that Agaricus bisporus and Cynara scolymus aqueous extracts, together with quercetin treatment, modified nuclear transcription factors leading to a significant decrease of intracellular lipid content and LDs size.In conclusion, these compounds may interfere and prevent the development of NAFLD in the presence of unfavourable genotype GG of PNPLA3. Quercetin and the aqueous extracts (A and M) may prevent the progression of liver damage related to NAFLD by two independent mechanisms: inhibition of lipogenesis by reducing SREBP-lc and promoting lipolysis through PPARα induction (<a class="elsevierStyleCrossRef" href="#f0020">Figure 4</a>). Further studies are required to clarify the molecular mechanism including their role in the oxidative stress. In addition, it would be needed to test the specific effect of single compounds which are included in the aqueous extracts described in this work.<elsevierMultimedia ident="f0020"></elsevierMultimedia>Abbreviations<ul class="elsevierStyleList" id="l0005"><li class="elsevierStyleListItem" id="u0005">•A: Cynara scolymus.</li><li class="elsevierStyleListItem" id="u0010">•AbAE: Agaricus bisporus aqueous extract.</li><li class="elsevierStyleListItem" id="u0015">•ACAT: Cholesterol acyltransferase.</li><li class="elsevierStyleListItem" id="u0020">•APOB: Apolipoprotein-B.</li><li class="elsevierStyleListItem" id="u0025">•APOE: Apolipoprotein-E.</li><li class="elsevierStyleListItem" id="u0030">•DAPI: 46-diamidino- 2-phenylindole.</li><li class="elsevierStyleListItem" id="u0035">•DGAT-1: Diacylglycerol acyltransferase-1.</li><li class="elsevierStyleListItem" id="u0040">•DGAT-2: Diacylglycerol acyltransferase-2.</li><li class="elsevierStyleListItem" id="u0045">•DMEM: Dulbecco’s Modified Eagle’s Medium.</li><li class="elsevierStyleListItem" id="u0050">•DMSO: Dimethyl sulfoxide.</li><li class="elsevierStyleListItem" id="u0055">•FASN: Fatty Acid Synthase.</li><li class="elsevierStyleListItem" id="u0060">•FBS: Fetal bovine serum.</li><li class="elsevierStyleListItem" id="u0065">•FFA: Free fatty acid.</li><li class="elsevierStyleListItem" id="u0070">•FITC: Fluorescein isothiocyanate.</li><li class="elsevierStyleListItem" id="u0075">•LDs: Lipid droplets.</li><li class="elsevierStyleListItem" id="u0080">•M: Agaricus Bisporus.</li><li class="elsevierStyleListItem" id="u0085">•MTTP: Microsomal triglyceride transfer protein.</li><li class="elsevierStyleListItem" id="u0090">•NAFLD: Non-alcoholic fatty liver disease,</li><li class="elsevierStyleListItem" id="u0095">•NASH: Non-alcoholic steatohepatitis.</li><li class="elsevierStyleListItem" id="u0100">•OA: Oleic acid.</li><li class="elsevierStyleListItem" id="u0105">•ORO: Oil Red O.</li><li class="elsevierStyleListItem" id="u0110">•PBS: Phosphate-buffered saline.</li><li class="elsevierStyleListItem" id="u0115">•PNPLA3: Patatin-like phospholipase domain-containing protein 3.</li><li class="elsevierStyleListItem" id="u0120">•PPAR-a: Peroxisome proliferator-activated receptor alpha.</li><li class="elsevierStyleListItem" id="u0125">•PPAR-?: Peroxisome proliferator-activated receptor gamma.</li><li class="elsevierStyleListItem" id="u0130">•q-PCR: Quantitative polymerase chain reaction.</li><li class="elsevierStyleListItem" id="u0135">•RT: Retro-transcription.</li><li class="elsevierStyleListItem" id="u0140">•SD: Standard deviation.</li><li class="elsevierStyleListItem" id="u0145">•SREBP: Sterol regulatory element binding protein-1.</li><li class="elsevierStyleListItem" id="u0150">•TG: Triglycerides.</li></ul>No Financial Disclose<ul class="elsevierStyleList" id="l0010"><li class="elsevierStyleListItem" id="u0155">•Financial support. None.</li></ul>Potential Competing InterestNone.Specific Author Contribution<ul class="elsevierStyleList" id="l0015"><li class="elsevierStyleListItem" id="u0160">•Planning and conducting the study: Ángela Rojas, Manuel Romero-Gómez.</li><li class="elsevierStyleListItem" id="u0165">•Drafting the manuscript: Ángela Rojas, Jose Antonio del Campo, Manuel Romero-Gomez.</li><li class="elsevierStyleListItem" id="u0170">•Interpreting data: Jose Antonio del Campo, Juan Bautista, Manuel Romero-Gomez.</li><li class="elsevierStyleListItem" id="u0175">•Performing in vitro studies: Ángela Rojas, Paloma Gallego, Antonio Gil-Gómez, Rocío Muñoz, Lourdes Rojas, Rosario Maldonado, Rocío Gallego-Durán, Marta García-Valdecasas.</li></ul>" "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres1190046" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abs0010" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1109524" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "s0005" "titulo" => "Introduction" ] 3 => array:3 [ "identificador" => "s0010" "titulo" => "Material and Methods" "secciones" => array:6 [ 0 => array:3 [ "identificador" => "s0015" "titulo" => "Cell Culture" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "s0020" "titulo" => "PNPLA3 genotyping" ] ] ] 1 => array:2 [ "identificador" => "s0025" "titulo" => "Preparation of aqueous extracts" ] 2 => array:2 [ "identificador" => "s0030" "titulo" => "Detection of LDs by Fluorescent Microscopy Oil Red O (ORO) cell staining." ] 3 => array:2 [ "identificador" => "s0035" "titulo" => "Fluorimetric determination of intracellular fat content - Nile red staining" ] 4 => array:2 [ "identificador" => "s0040" "titulo" => "RNA isolation, retro-transcription and quantitative polymerase chain reaction (q-PCR)" ] 5 => array:2 [ "identificador" => "s0045" "titulo" => "Statistical Analysis" ] ] ] 4 => array:3 [ "identificador" => "s0050" "titulo" => "Results" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "s0055" "titulo" => "Huh7.5 PNPLA3 genotype" ] 1 => array:2 [ "identificador" => "s0060" "titulo" => "Oleic acid-induced intracellular lipid accumulation in Huh7.5 cells" ] 2 => array:2 [ "identificador" => "s0065" "titulo" => "Effects of Quercetin and water-soluble extracts from mushroom and artichoke on hepatic lipid accumulation" ] 3 => array:2 [ "identificador" => "s0070" "titulo" => "Aqueous extracts modulated lipogenesis-related gene expression" ] ] ] 5 => array:2 [ "identificador" => "s0075" "titulo" => "Discussion" ] 6 => array:2 [ "identificador" => "s0080" "titulo" => "Abbreviations" ] 7 => array:2 [ "identificador" => "s0085" "titulo" => "No Financial Disclose" ] 8 => array:2 [ "identificador" => "s0090" "titulo" => "Potential Competing Interest" ] 9 => array:2 [ "identificador" => "s0095" "titulo" => "Specific Author Contribution" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2017-05-13" "fechaAceptado" => "2017-06-27" "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1109524" "palabras" => array:8 [ 0 => "Steatosis" 1 => "Lipid droplets" 2 => "Triglycerides" 3 => "Quercetin" 4 => "Cynara scolymus" 5 => "Agaricus Bisporus" 6 => "Mushroom" 7 => "Artichoke" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Background & aims. G-allele of PNPLA3 (rs738409) favours triglycerides accumulation and steatosis. In this study, we examined the effect of quercetin and natural extracts from mushroom and artichoke on reducing lipid accumulation in hepatic cells.Material and methods. Huh7.5 cells were exposed to oleic acid (OA) and treated with quercetin and extracts to observe the lipid accumulation, the intracellular-TG concentration and the LD size. Sterol regulatory element binding proteins-1 (SREBP-1), peroxisome proliferator-activated receptor (PPARα-γ) and cholesterol acyltransferase (ACAT) gene expression levels were analysed.Results. Quercetin decreased the intracellular lipids, LD size and the levels of intracellular-TG through the down-regulation of SREBP-1c, PPARγand ACAT1 increasing PPARα. The natural-extracts suppressed OA-induced lipid accumulation and the intracellular-TG. They down-regulate the hepatic lipogenesis through SREBP-1c, besides the activation of lipolysis through the increasing of PPARα expression.Conclusions. Quercetin and the aqueous extracts decrease intracellular lipid accumulation by down-regulation of lipogenesis and up-regulation of lipolysis." ] ] "multimedia" => array:4 [ 0 => array:7 [ "identificador" => "f0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 521 "Ancho" => 743 "Tamanyo" => 54641 ] ] "descripcion" => array:1 [ "en" => "Untreated Huh7.5 (A) and Huh7.5 cells cultured at OA concentrations 1 mM, for 48 hours (B). LDs and nuclei were stained with ORO (red) and Dapi (blue), respectively. Images were acquired with a fluorescence microscope (OLIMPUS BX41) equipped with the standard epifluorescence filter set up for DAPI and FITC under oil with a 100x plan apochromat objective. C. Intracellular triglycerides concentration. AdipoRed™ Assay of Huh7.5 and OA-Huh7.5 cells. The intracellular triglycerides were stained and the concentration of triglycerides was quantified by fluorescence. (Huh7.5 fold=1) (***p < 0.01). Data are presented as the mean values ± SD obtained from three independent experiments. D. (A) mRNA gene expression levels of DGAT-1, DGAT-2, MTTP, FASN, apoE and apoB were determined by RT-PCR. Results were normalized using GAPDH and Huh7.5 non-treated cells were used as reference. *p < 0.05; **p < 0.01 and ***p < 0.001. Data are the mean value ± SD obtained from three independent experiments." ] ] 1 => array:7 [ "identificador" => "f0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 522 "Ancho" => 665 "Tamanyo" => 48239 ] ] "descripcion" => array:1 [ "en" => "A. Huh7.5 (a) and OA-Huh7.5 (e) cells treated with quercetin 50 µМ (b-f), aqueous extracts from mushroom (M) (c-g) and artichoke (A) (d-h) (0.1 mg/mL), for 48 h. LDs and nuclei were stained with ORO (red) and Dapi (blue), respectively. Images were taken using a fluorescence microscope (OLIMPUS BX41) equipped with a 100x objective and the standard epifluorescence filter set up for DAPI and FITC. B. LDs size were measured by Imaging Software cell^F Software. Results are expressed as fold-area µm<a class="elsevierStyleCrossRef" href="#bib0015">3</a>. C. Intracellular triglycerides concentration. AdipoRed Assay. The intracellular triglycerides were stained and the concentration of triglycerides was quantifed by fluorescence (Huh7.5 fold = 1). Data are presented as the mean values ± SD obtained from three independent experiments. Experiments were performed in triplicate. (*) p < 0.05; (**) p < 0.01 (***) p < 0.001." ] ] 2 => array:7 [ "identificador" => "f0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 298 "Ancho" => 657 "Tamanyo" => 34886 ] ] "descripcion" => array:1 [ "en" => "A.mRNA gene expression levels of SREBP-1c, PPARγand PPARαwere determined by RT-PCR. B. ACAT-1 mRNA gene expresision levels. Results were normalized using GAPDH and Huh7.5 non-treated cells were used as reference. *p < 0.05; **p < 0.01 and ***p < 0.001. Data are the mean value ± SD obtained from three independent experiments." ] ] 3 => array:7 [ "identificador" => "f0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 231 "Ancho" => 320 "Tamanyo" => 10750 ] ] "descripcion" => array:1 [ "en" => "Possible mechanisms about the beneficial effects of quercetin and aqueous extracts in NAFLD." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bs0010" "bibliografiaReferencia" => array:43 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Non-alcoholic fatty liver disease 2015" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Ahmed M." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "World J Hepatol" "fecha" => "2015" "volumen" => "18" "paginaInicial" => "1450" "paginaFinal" => "1459" ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Postic C." 1 => "Girard J." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1172/JCI34275" "Revista" => array:6 [ "tituloSerie" => "J Clin Invest" "fecha" => "2008" "volumen" => "118" "paginaInicial" => "829" "paginaFinal" => "838" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18317565" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Interrelationship between fatty liver and insulin resistance in the development of type 2 diabetes" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Sung K.C." 1 => "Kim S.H." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/jc.2010-2190" "Revista" => array:6 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "2011" "volumen" => "96" "paginaInicial" => "1093" "paginaFinal" => "1097" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21252243" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The histologic spectrum of nonalcoholic fatty liver disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "Contos M.J." 1 => "Choudhury J." 2 => "Mills A.S." 3 => "Sanyal A.J." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.cld.2004.04.013" "Revista" => array:6 [ "tituloSerie" => "Clin Liver Dis" "fecha" => "2004" "volumen" => "8" "paginaInicial" => "481" "paginaFinal" => "500" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15331059" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Human fatty liver disease: old questions and new insights" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "Cohen J.C." 1 => "Horton J.D." 2 => "Hobbs H.H." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1126/science.1204265" "Revista" => array:6 [ "tituloSerie" => "Science" "fecha" => "2011" "volumen" => "332" "paginaInicial" => "1519" "paginaFinal" => "1523" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21700865" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0030" "etiqueta" => "6." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Recent insights into hepatic lipid metabolism in non-alcoholic fatty liver disease (NAFLD)" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "Musso G." 1 => "Gambino R." 2 => "Cassader M." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.plipres.2008.08.001" "Revista" => array:6 [ "tituloSerie" => "Prog Lipid Res" "fecha" => "2009" "volumen" => "48" "paginaInicial" => "1" "paginaFinal" => "26" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18824034" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0035" "etiqueta" => "7." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Inhibition of ceramide de novo synthesis reduces liver lipid accumulation in rats with nonalcoholic fatty liver disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Kurek K." 1 => "Piotrowska D.M." 2 => "Wiesiolek-Kurek P." 3 => "Lukaszuk B." 4 => "Chabowski A." 5 => "Górski J." 6 => "Zendzian-Piotrowska M." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/liv.12331" "Revista" => array:6 [ "tituloSerie" => "Liver Int" "fecha" => "2014" "volumen" => "34" "paginaInicial" => "1074" "paginaFinal" => "1083" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24106929" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0040" "etiqueta" => "8." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Inhibitory effect of blueberry polyphenolic compounds on oleic acid-induced hepatic steatosis in vitro" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:7 [ 0 => "Liu Y." 1 => "Wang D." 2 => "Zhang D." 3 => "Lv Y." 4 => "Wei Y." 5 => "Wu W." 6 => "Zhou F." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "J Agric Food Chem" "fecha" => "2011" "volumen" => "23" "paginaInicial" => "12254" "paginaFinal" => "12263" ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0045" "etiqueta" => "9." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Curcumin decreases oleic acid-induced lipid accumulation via AMPK phosphorylation in hepatocarcinoma cells" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:7 [ 0 => "Kang O.H." 1 => "Kim S.B." 2 => "Seo Y.S." 3 => "Joung D.K." 4 => "Mun S.H." 5 => "Choi J.G." 6 => "Lee Y.M." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Eur Rev Med Pharmacol Sci" "fecha" => "2013" "volumen" => "17" "paginaInicial" => "2578" "paginaFinal" => "2586" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24142602" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0050" "etiqueta" => "10." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pinus densiflora Sieb. et Zucc. alleviates lipogenesis and oxidative stress during oleic acid-induced steatosis in HepG2 cells" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "Hwang Y.J." 1 => "Wi H.R." 2 => "Kim H.R." 3 => "Park K.W." 4 => "Hwang K.A." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3390/nu6072956" "Revista" => array:6 [ "tituloSerie" => "Nutrients" "fecha" => "2014" "volumen" => "6" "paginaInicial" => "2956" "paginaFinal" => "2972" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25057104" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0055" "etiqueta" => "11." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Quercetin improves insulin resistance and hepatic lipid accumulation in vitro in a NAFLD cell model" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:7 [ 0 => "Li X." 1 => "Wang R." 2 => "Zhou N." 3 => "Wang X." 4 => "Liu Q." 5 => "Bai Y." 6 => "Liu Z." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3892/br.2012.27" "Revista" => array:6 [ "tituloSerie" => "Biomed Rep" "fecha" => "2013" "volumen" => "1" "paginaInicial" => "71" "paginaFinal" => "76" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24648896" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0060" "etiqueta" => "12." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Meta-analysis of traditional herbal medicine in the treatment of nonalcoholic fatty liver disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "Peng H." 1 => "He Y." 2 => "Zheng G." 3 => "Zhang W." 4 => "Yao Z." 5 => "Xie W." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Cell Mol Biol" "fecha" => "2016" "volumen" => "62" "paginaInicial" => "88" "paginaFinal" => "95" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27188741" "web" => "Medline" ] ] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0065" "etiqueta" => "13." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Natural antioxidants for non-alcoholic fatty liver disease: molecular targets and clinical perspectives" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "Salomone F." 1 => "Godos J." 2 => "Zelber-Sagi S." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/liv.13035" "Revista" => array:6 [ "tituloSerie" => "Liver Int" "fecha" => "2016" "volumen" => "36" "paginaInicial" => "5" "paginaFinal" => "20" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26725890" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0070" "etiqueta" => "14." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The genetics of NAFLD" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Anstee Q.M." 1 => "Day C.P." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/nrgastro.2013.182" "Revista" => array:6 [ "tituloSerie" => "Nat Rev Gastroenterol Hepatol" "fecha" => "2013" "volumen" => "10" "paginaInicial" => "645" "paginaFinal" => "655" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24061205" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0075" "etiqueta" => "15." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:7 [ 0 => "Romeo S." 1 => "Kozlitina J." 2 => "Xing C." 3 => "Pertsemlidis A." 4 => "Cox D." 5 => "Pennacchio L.A." 6 => "Boerwinkle E." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/ng.257" "Revista" => array:6 [ "tituloSerie" => "Nat Genet" "fecha" => "2008" "volumen" => "40" "paginaInicial" => "1461" "paginaFinal" => "1465" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18820647" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0080" "etiqueta" => "16." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:7 [ 0 => "He S." 1 => "McPhaul C." 2 => "Li J.Z." 3 => "Garuti R." 4 => "Kinch L." 5 => "Grishin N.V." 6 => "Cohen J.C." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1074/jbc.M109.064501" "Revista" => array:6 [ "tituloSerie" => "J Biol Chem" "fecha" => "2010" "volumen" => "285" "paginaInicial" => "6706" "paginaFinal" => "6715" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20034933" "web" => "Medline" ] ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0085" "etiqueta" => "17." "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "BasuRay S, Smagris E, Cohen JC, Hobbs HH. The PNPLA3 Variant Associated with Fatty Liver Disease (I148M) Accumulates on Lipid Droplets by Evading Ubiquitylation. Hepatology 2017 [Epub ahead of print]." ] ] ] 17 => array:3 [ "identificador" => "bib0090" "etiqueta" => "18." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "PNPLA3 rs738409 causes steatosis according to viral & IL28B genotypes in hepatitis C" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:7 [ 0 => "Ampuero J." 1 => "Del Campo J.A." 2 => "Rojas L." 3 => "García-Lozano J.R." 4 => "Solá R." 5 => "Andrade R." 6 => "Pons J.A." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Ann Hepatol" "fecha" => "2014" "volumen" => "13" "paginaInicial" => "356" "paginaFinal" => "363" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24927606" "web" => "Medline" ] ] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib0095" "etiqueta" => "19." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of intracellular lipid accumulation in a new model of non-alcoholic fatty liver disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "Chavez-Tapia N.C." 1 => "Rosso N." 2 => "Tiribelli C." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1186/1471-230X-12-20" "Revista" => array:5 [ "tituloSerie" => "BMC Gastroenterol" "fecha" => "2012" "volumen" => "12" "paginaInicial" => "20" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22380754" "web" => "Medline" ] ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib0100" "etiqueta" => "20." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Preparation and Characterisation of Selenium-Enriched Mushroom Aqueous Enzymatic Extracts (MAEE) Obtained from the White Button Mushroom (Agaricus bisporus)" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:7 [ 0 => "Cremades O." 1 => "Diaz-Herrero M.M." 2 => "Carbonero-Aguilar P." 3 => "Gutierrez-Gil J.F." 4 => "Fontiveros E." 5 => "Rodríguez-Morgado B." 6 => "Parrado J." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Food Chemistry" "fecha" => "2012" "volumen" => "133" "paginaInicial" => "1538" "paginaFinal" => "1543" ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib0105" "etiqueta" => "21." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Inhibited proliferation of cyclooxygenase-2 expressing human hepatoma cells by NS-398 a selective COX-2 inhibitor" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "Hu K.Q." 1 => "Yu C.H." 2 => "Mineyama Y." 3 => "McCracken J.D." 4 => "Hillebrand D.J." 5 => "Hasan M." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Int J Oncol" "fecha" => "2003" "volumen" => "22" "paginaInicial" => "757" "paginaFinal" => "763" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12632065" "web" => "Medline" ] ] ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib0110" "etiqueta" => "22." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Monocyte chemoattractant protein-1 secreted by adipose tissue induces direct lipid accumulation in hepatocytes" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:7 [ 0 => "Clement S." 1 => "Juge-Aubry C." 2 => "Sgroi A." 3 => "Conzelmann S." 4 => "Pazienza V." 5 => "Pittet-Cuenod B." 6 => "Meier C.A." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/hep.22404" "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "2008" "volumen" => "48" "paginaInicial" => "799" "paginaFinal" => "807" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18570214" "web" => "Medline" ] ] ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib0115" "etiqueta" => "23." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Nile Red binding to HepG2 cells: an improved assay for in vitro studies of hepatosteatosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:7 [ 0 => "McMillian M.K." 1 => "Grant E.R." 2 => "Zhong Z." 3 => "Parker J.B." 4 => "Li L." 5 => "Zivin R.A." 6 => "Burczynski M.E." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1089/109793301753407948" "Revista" => array:7 [ "tituloSerie" => "In Vitr Mol Toxicol" "fecha" => "2001" "volumen" => "14" "numero" => "3" "paginaInicial" => "177" "paginaFinal" => "190" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11846991" "web" => "Medline" ] ] ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib0120" "etiqueta" => "24." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Single-step method of RNA isolation by acid guanidinium thiocyanate-phenolchloroform extraction" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Chomczynski P." 1 => "Sacchi N." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1006/abio.1987.9999" "Revista" => array:6 [ "tituloSerie" => "Anal Biochem" "fecha" => "1987" "volumen" => "162" "paginaInicial" => "156" "paginaFinal" => "159" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2440339" "web" => "Medline" ] ] ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib0125" "etiqueta" => "25." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Flavonoids and Related Compounds in Non-Alcoholic Fatty Liver Disease Therapy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "Pisonero-Vaquero S." 1 => "Gonzalez-Gallego J." 2 => "Sanchez-Campos S." 3 => "Garcia-Mediavilla M.V." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Curr Med Chem" "fecha" => "2015" "volumen" => "22" "paginaInicial" => "2991" "paginaFinal" => "3012" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26242257" "web" => "Medline" ] ] ] ] ] ] ] ] 25 => array:3 [ "identificador" => "bib0130" "etiqueta" => "26." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A CONSORTcompliant randomized double-blind placebo-controlled pilot trial of purified anthocyanin in patients with nonalcoholic fatty liver disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "Zhang P.W." 1 => "Chen F.X." 2 => "Li D." 3 => "Ling W.H." 4 => "Guo H.H." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Medicine (Baltimore)" "fecha" => "2015" "volumen" => "94" "paginaInicial" => "e758" ] ] ] ] ] ] 26 => array:3 [ "identificador" => "bib0135" "etiqueta" => "27." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Vitamin E therapy on aminotransferase levels in NAFLD/NASH patients" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Ji H.F." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.nut.2015.02.010" "Revista" => array:5 [ "tituloSerie" => "Nutrition" "fecha" => "2015" "volumen" => "31" "paginaInicial" => "899" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25933502" "web" => "Medline" ] ] ] ] ] ] ] ] 27 => array:3 [ "identificador" => "bib0140" "etiqueta" => "28." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Anthocyanin inhibits high glucose-induced hepatic mtGPAT1 activation and prevents fatty acid synthesis through PKC" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "Guo H." 1 => "Li D." 2 => "Ling W." 3 => "Feng X." 4 => "Xia M." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1194/jlr.M013375" "Revista" => array:6 [ "tituloSerie" => "J Lipid Res" "fecha" => "2011" "volumen" => "52" "paginaInicial" => "908" "paginaFinal" => "922" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21343633" "web" => "Medline" ] ] ] ] ] ] ] ] 28 => array:3 [ "identificador" => "bib0145" "etiqueta" => "29." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Grape seed proanthocyanidins repress the hepatic lipid regulators miR-33 and miR-122 in rats" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Baselga-Escudero L." 1 => "Bladé C." 2 => "Ribas-Latre A." 3 => "Casanova E." 4 => "Salvadó M.J." 5 => "Arola L." 6 => "Arola-Arnal A." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/mnfr.201200237" "Revista" => array:6 [ "tituloSerie" => "Mol Nutr Food Res" "fecha" => "2012" "volumen" => "56" "paginaInicial" => "1636" "paginaFinal" => "1646" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22965541" "web" => "Medline" ] ] ] ] ] ] ] ] 29 => array:3 [ "identificador" => "bib0150" "etiqueta" => "30." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "HG. 3-Caffeoyl 4-dihydrocaffeoylquinic acid from Salicornia herbacea attenuates high glucose-induced hepatic lipogenesis in human HepG2 cells through activation of the liver kinase B1 and silent information regulator T1/AMPK-dependent pathway" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:7 [ 0 => "PilHwang Y." 1 => "Gyun Kim H." 2 => "Choi J.H." 3 => "Truong Do M." 4 => "Tran T.P." 5 => "Chun H.K." 6 => "Chung Y.C." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/mnfr.201200529" "Revista" => array:6 [ "tituloSerie" => "Mol Nutr Food Res" "fecha" => "2013" "volumen" => "57" "paginaInicial" => "471" "paginaFinal" => "482" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23349077" "web" => "Medline" ] ] ] ] ] ] ] ] 30 => array:3 [ "identificador" => "bib0155" "etiqueta" => "31." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Ellagic acid improves hepatic steatosis and serum lipid composition through reduction of serum resistin levels and transcriptional activation of hepatic ppara in obese diabetic KK-A(y) mice" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "Yoshimura Y." 1 => "Nishii S." 2 => "Zaima N." 3 => "Moriyama T." 4 => "Kawamura Y." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.bbrc.2013.03.100" "Revista" => array:6 [ "tituloSerie" => "Biochem Biophys Res Commun" "fecha" => "2013" "volumen" => "434" "paginaInicial" => "486" "paginaFinal" => "491" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23583377" "web" => "Medline" ] ] ] ] ] ] ] ] 31 => array:3 [ "identificador" => "bib0160" "etiqueta" => "32." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Resveratrol inhibits fatty acid and triacylglycerol synthesis in rat hepatocytes" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Gnoni G.V." 1 => "Paglialonga G." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1365-2362.2008.02077.x" "Revista" => array:6 [ "tituloSerie" => "Eur J Clin Invest" "fecha" => "2009" "volumen" => "39" "paginaInicial" => "211" "paginaFinal" => "218" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19260951" "web" => "Medline" ] ] ] ] ] ] ] ] 32 => array:3 [ "identificador" => "bib0165" "etiqueta" => "33." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Resveratrol inhibits the expression of SREBP1 in cell model of steatosis via Sirt1-FOXO1 signaling pathway" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "Wang G.L." 1 => "Fu Y.C." 2 => "Xu W.C." 3 => "Feng Y.Q." 4 => "Fang S.R." 5 => "Zhou X.H." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.bbrc.2009.01.163" "Revista" => array:6 [ "tituloSerie" => "Biochem Biophys Res Commun" "fecha" => "2009" "volumen" => "380" "paginaInicial" => "644" "paginaFinal" => "649" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19285015" "web" => "Medline" ] ] ] ] ] ] ] ] 33 => array:3 [ "identificador" => "bib0170" "etiqueta" => "34." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Resveratrol improves non-alcoholic fatty liver disease by activating AMP-activated protein kinase" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "Shang J." 1 => "Chen L.L." 2 => "Xiao F.X." 3 => "Sun H." 4 => "Ding H.C." 5 => "Xiao H." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1745-7254.2008.00807.x" "Revista" => array:6 [ "tituloSerie" => "Acta Pharmacol Sin" "fecha" => "2008" "volumen" => "29" "paginaInicial" => "698" "paginaFinal" => "706" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18501116" "web" => "Medline" ] ] ] ] ] ] ] ] 34 => array:3 [ "identificador" => "bib0175" "etiqueta" => "35." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Quercetin ameliorate insulin resistance and up-regulates cellular antioxidants during oleic acid induced hepatic steatosis in HepG2 cells" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "Vidyashankar S." 1 => "Sandeep Varma R." 2 => "Patki P.S." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.tiv.2013.01.014" "Revista" => array:6 [ "tituloSerie" => "Toxicol In Vitro" "fecha" => "2013" "volumen" => "27" "paginaInicial" => "945" "paginaFinal" => "953" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23348005" "web" => "Medline" ] ] ] ] ] ] ] ] 35 => array:3 [ "identificador" => "bib0180" "etiqueta" => "36." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The Potential of Flavonoids in the Treatment of Non-alcoholic Fatty Liver Disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "Van De Wier B." 1 => "Koek G.H." 2 => "Bast A." 3 => "Haenen G.R." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1080/10408398.2014.952399" "Revista" => array:6 [ "tituloSerie" => "Crit Rev Food Sci Nutr" "fecha" => "2017" "volumen" => "57" "paginaInicial" => "834" "paginaFinal" => "855" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25897647" "web" => "Medline" ] ] ] ] ] ] ] ] 36 => array:3 [ "identificador" => "bib0185" "etiqueta" => "37." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effects of resveratrol and other polyphenols in hepatic steatosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "Aguirre L." 1 => "Portillo M.P." 2 => "Hijona E." 3 => "Bujanda L." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3748/wjg.v20.i23.7366" "Revista" => array:6 [ "tituloSerie" => "World J Gastroenterol" "fecha" => "2014" "volumen" => "20" "paginaInicial" => "7366" "paginaFinal" => "7380" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24966607" "web" => "Medline" ] ] ] ] ] ] ] ] 37 => array:3 [ "identificador" => "bib0190" "etiqueta" => "38." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Fatty Acid-Regulated Transcription Factors in the Liver" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "Jump D.B." 1 => "Tripathy S." 2 => "Depner C.M." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1146/annurev-nutr-071812-161139" "Revista" => array:6 [ "tituloSerie" => "Annu Rev Nutr" "fecha" => "2013" "volumen" => "33" "paginaInicial" => "249" "paginaFinal" => "269" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23528177" "web" => "Medline" ] ] ] ] ] ] ] ] 38 => array:3 [ "identificador" => "bib0195" "etiqueta" => "39." 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"referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Amelioration of free fatty acid-induced fatty liver by quercetin-3-O-b-D-glucuronide through modulation of peroxisome proliferator-activated receptor-alpha/sterol regulatory element-binding protein-1c signaling" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "Wang L.L." 1 => "Zhang Z.C." 2 => "Hassan W." 3 => "Li Y." 4 => "Liu J." 5 => "Shang J." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/hepr.12557" "Revista" => array:6 [ "tituloSerie" => "Hepatol Res" "fecha" => "2016" "volumen" => "46" "paginaInicial" => "225" "paginaFinal" => "238" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26190035" "web" => "Medline" ] ] ] ] ] ] ] ] 42 => array:3 [ "identificador" => "bib0215" "etiqueta" => "43." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Review. 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Ángela Rojas*, Paloma Gallego**, Antonio Gil-Gómez*, Rocío Muñoz-Hernández*, Lourdes Rojas*, Rosario Maldonado***, Rocío Gallego-Durán*, Marta García-Valdecasas*, José A. Del Campo**,****, Juan D. Bautista****, Manuel Romero-Gómez

Corresponding author

mromerogomez@us.es

Corresponding author.

* Laboratorio de Investigación clínica y traslacional en enfermedades hepáticas y digestivas y CIBERehd. Instituto de Biomedicina de Sevilla (IBiS). Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain

** UGC de enfermedades hepáticas y digestivas, CIBERehd. Hospital Universitario de Valme, Sevilla, Spain

*** Unidad de Farmacología Clínica y Experimental. Hospital Universitario de Valme, Seville, Spain

**** Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, Seville, Spain

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          "en" => "<p id="sp0020" class="elsevierStyleSimplePara elsevierViewall">Possible mechanisms about the beneficial effects of quercetin and aqueous extracts in NAFLD&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="s0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0015">Introduction</span><p id="p0005" class="elsevierStylePara elsevierViewall">Non-alcoholic fatty liver disease &#40;NAFLD&#41; is defined as the accumulation of excessive fat in the liver in the absence of excessive drinking of alcohol&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> It has been included as a metabolic abnormality such as obesity&#44; type 2 diabetes&#44; arterial hypertension&#44; and hypertriglyceridemia&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> NAFLD encompasses a wide spectrum of liver damage ranging from simple steatosis to non-alcoholic steatohepatitis &#40;NASH&#41;&#44; advanced fibrosis&#44; and rarely&#44; progression to cirrhosis and hepatocellular carcinoma&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="p0010" class="elsevierStylePara elsevierViewall">Hepatic steatosis can either be a benign&#44; non-inflammatory condition&#44; or can be associated with non-alcoholic steatohepatitis &#40;NASH&#41;&#46; The earliest stage is characterized by the excessive triglycerides &#40;TGs&#41; accumulation as lipid droplets &#40;LDs&#41; in the cytoplasm of hepatocytes&#46; Hepatic steatosis is often self-limited&#44; however it can progress to NASH&#44; which is known by the presence of hepatocyte injury &#40;hepatocyte ballooning and cell death&#41;&#44; inflammatory infiltrate&#44; and&#47;or collagen deposition &#40;fibrosis&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> It has been postulated that the inhibition of excessive lipid synthesis and uptake could be an effective intervention for NASH&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><p id="p0015" class="elsevierStylePara elsevierViewall">Dietary fat is one of the most important environmental factors associated with the incidence of NAFLD&#46; The search of functional food ingredients such as herbal extracts or flavonoids capable to suppress the accumulation of hepatic lipid<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8</span></a>&#8211;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> by the modulation of several pathways is ongoing&#46; Several polyphenols and phenolic compounds&#44; such anthocyanins&#44; curcumin&#44; resveratrol&#44; silymarin and those present in coffee and tea have been proposed as NAFLD treatment but the varying bioavailability remains poor&#44; so further studies are needed for the future clinical applications&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a></p><p id="p0020" class="elsevierStylePara elsevierViewall">Steatosis could be modulated by genetic susceptibility&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> In 2008&#44; Romeo&#44; <span class="elsevierStyleItalic">et al&#46;</span> performed an independent genome-wide association study to identify genetic determinants of liver steatosis&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> The author figured out that the polymorphism rs738409 C&#62;G in <span class="elsevierStyleItalic">PNPLA3</span> gene was robustly associated with an increased risk for hepatic steatosis&#46; Patatin-like phospholipase domain-containing protein 3 &#40;PNPLA3&#41; is a transmembrane protein expressed prominently in hepatocytes and the substitution I148M has been suggested to impair TG hydrolysis in hepatocytes&#44; favouring its accumulation&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> Recently it has been proposed that PNPLA3-148M evade ubiquitylation and proteasomal degradation&#44; resulting in the accumulation of PNPLA3-148M on the surfaces of lipid droplets impairing TGs mobilization from LDs&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> The discovery of new drugs to reduce the risk of NAFLD would be useful considering the genetics factors&#46; The purposes of this study were to elucidate the role of quercetin and other water-soluble extracts in an <span class="elsevierStyleItalic">in-vitro</span> model with unfavourable genotype GG for <span class="elsevierStyleItalic">PNPLA3&#46;</span><a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p></span><span id="s0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0020">Material and Methods</span><span id="s0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0025">Cell Culture</span><p id="p0025" class="elsevierStylePara elsevierViewall">Huh7&#46;5 cells were routinely cultured in DMEM &#40;ThermoFisher&#44; MA&#44; USA&#41; supplemented with 10&#37; FBS and 1&#37; penicillin-streptomycin in an incubator under an atmosphere of 5&#37; CO2 at 37 &#176;C&#46; The Huh7&#46;5 cell model of OA-induced intracellular lipid accumulation was developed as previously described&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> Cells were cultured with 1mM of Oleic acid for 48 h&#46; Control cells were treated with FFA-free medium containing the vehicle dimethyl sulfoxide &#40;DMSO&#41;&#46;</p><span id="s0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0030"><span class="elsevierStyleItalic">PNPLA3</span> genotyping</span><p id="p0030" class="elsevierStylePara elsevierViewall">DNA from cells was extracted using the DNA isolation Kit with the MagNA Pure LC Instruments &#40;Roche&#41;&#46; The rs738409 SNPs were analysed using the StepOnePlus Real Time PCR System &#40;Applied Biosystem&#44; Foster City&#44; USA&#41; with a Taqman SNP Genotyping Assay&#44; using published sequences from the NCBI Entrez SNP Database &#40;<a href="http://www.ncbi.nlm.nih.gov/sites/entrez">www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;sites&#47;entrez</a>&#41; &#40;rs738409&#58; 5&#8217;-AAG-GAGGGATAAGGCCACTGTA-3 as forward and 5&#8217;-CTTTCACAGGCCTTGGTATGTTC-3&#8217; as reverse primer&#41;&#46;</p></span></span><span id="s0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0035">Preparation of aqueous extracts</span><p id="p0035" class="elsevierStylePara elsevierViewall">White button mushrooms <span class="elsevierStyleItalic">&#40;Agaricus bisporus&#41;</span> were used as raw material after cultivation in a pilot plant at the University of Seville &#40;Spain&#41;&#44; according to standard procedures&#46; All chemicals used were of analytical grade&#46; <span class="elsevierStyleItalic">Agaricus bisporus</span> Aqueous Extract &#40;AbAE&#41; was obtained by an enzymatic procedure based on the protocol described by Cremades and colleagues&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> Briefly&#44; after A&#46; bisporus homogenization &#40;10g &#43; 10 mL distilled water&#41; and enzymatic digestion with a mixture of glucanase and chitinase enzymes &#40;Novo Nordisk&#174;&#44; Denmark&#41; at pH &#61; 5&#44; temperature 55 &#176;C and an enzyme&#47;substrate ratio of 0&#46;01&#44; for 24 h&#46; Finally&#44; temperature was raised up to 90 &#176;C for 120 min to inactivate the enzymes&#46; After cooling to room temperature&#44; pH was adjusted to 7&#46;0 with 1M NaOH and centrifuged at 8000 &#215; g&#46; The supernatant was collected and filtered through a 0&#46;2 <span class="elsevierStyleItalic">&#181;</span>m membrane&#44; using the filtrate as &#8220;crude AbAE&#8221; for activity assays&#46; <span class="elsevierStyleItalic">Cynara scolymus</span> aqueous extracts were obtained by a similar procedure but using a mixture of celluloses and proteases as hydrolytic agent&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a></p></span><span id="s0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0040">Detection of LDs by Fluorescent Microscopy Oil Red O &#40;ORO&#41; cell staining&#46;</span><p id="p0040" class="elsevierStylePara elsevierViewall">Neutral lipids stored into the LDs were visualized by fluorescence microscopy using ORO staining &#40;SigmaAldrich&#44; MO&#44; USA&#41;&#44; a vital lipophilic dye used to label fat accumulation in the cytosol&#44; according to Hu and colleagues&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> To analyze fat accumulation 20&#44;000 Huh7&#46;5 cells were seeded and grown on coverslips in 24 wells plate&#46; Huh7&#46;5 cells were cultured in the presence of oleic acid 1mM diluted in DMSO &#40;less than 0&#46;01&#37; of total volume&#41; and treated for 48h with 50 <span class="elsevierStyleItalic">&#181;</span>M of quercetin &#40;HWI ANALYTIK&#44; GmbH&#44; Germany&#41; or 0&#46;1 mg&#47;mL of water-soluble extract from <span class="elsevierStyleItalic">A&#46; Bisporus</span> &#40;M&#41; or <span class="elsevierStyleItalic">Cynara scolymus</span> &#40;A&#41;&#46; The cells were rinsed two times with phosphate-buffered saline &#40;PBS&#41; pH 7&#46;4&#44; fixed with 4&#37; paraformaldehyde in PBS for 10min and permeabilised with 0&#46;2&#37; Triton X-100 for 2 min&#46; Nuclei cells were stained with 46-diamidino- 2phenylindole &#40;DAPI&#41; for 30min at room temperature&#44; and neutral lipids were stained with ORO as previously described&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> Images were acquired with a fluorescence microscope &#40;OLYMPUS BX41&#41; equipped with the standard epifluorescence filter set up for DAPI and FITC&#46; For determination of LD diameter images were captured under oil with a 100x plan apochromat objective&#46; Analyses were performed on three independent experiments measuring at least 100 cells for each treatment using Imaging Software cell&#94;F &#40;Olympus&#44; Tokyo&#44; Japan&#41;&#46;</p></span><span id="s0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0045">Fluorimetric determination of intracellular fat content - Nile red staining</span><p id="p0045" class="elsevierStylePara elsevierViewall">The intracellular fat content was determined fluorimetrically based on Nile Red staining&#44; a vital lipophilic dye used to label fat accumulation in the cytosol&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> Ten thousand Huh7&#46;5 cells were grown in 96 plate wells&#44; exposed to oleic acid and treated with quercetin and water-soluble M or A for 48 h&#46; AdipoRed&#8482; Reagent &#40;Lonza&#44; Basel&#44; Switzerland&#41; was added to each well and incubated at room temperature for 10 min&#46; Intensity fluorescence was quantified using Synergy HT at 485&#47;572 nm &#40;BioTeK&#44; VT&#44; USA&#41; and normalized to protein concentration&#46;</p></span><span id="s0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0050">RNA isolation&#44; retro-transcription and quantitative polymerase chain reaction &#40;q-PCR&#41;</span><p id="p0050" class="elsevierStylePara elsevierViewall">Total RNA was extracted from the above-treated cells using the guanidine isothiocyanate method&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> RNA samples were treated with DNaseI&#46; Total RNA was subjected to reverse transcription &#40;RT&#41; using commercially available kits &#40;QuantiTect Rev&#46; Transcription Kit&#59; Qiagen&#44; Hilden&#44; Germany&#41; according to the manufacturer&#8217;s instructions&#46; <span class="elsevierStyleItalic">SREBP-lc&#44; PPAR&#947;&#44; PPAR&#945;&#44; ACAT&#44; DGAT-1&#44; DGAT-2&#44; FASN&#44; MTTP&#44; APOB</span> and <span class="elsevierStyleItalic">APOE</span> gene expression levels were analysed using commercial oligonucleotides &#40;Qiagen&#44; Hilden&#44; Germany&#41;&#46;</p></span><span id="s0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0055">Statistical Analysis</span><p id="p0055" class="elsevierStylePara elsevierViewall">Continuous variables are described as means &#177; SD of minimum three independent experiments&#46; The Student t-test was used for comparisons between groups&#46; P values P &#60; 0&#46;05 &#40;&#42;&#41; p &#60; 0&#46;01 &#40;&#42;&#42;&#41; and p &#60; 0&#46;001 &#40;&#42;&#42;&#42;&#41; were considered statistically significant&#46;</p></span></span><span id="s0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0060">Results</span><span id="s0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0065">Huh7&#46;5 <span class="elsevierStyleItalic">PNPLA3</span> genotype</span><p id="p0060" class="elsevierStylePara elsevierViewall">Huh7&#46;5 cells presented unfavourable genotype GG for <span class="elsevierStyleItalic">PNPLA3</span> as previously was showed&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p></span><span id="s0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0070">Oleic acid-induced intracellular lipid accumulation in Huh7&#46;5 cells</span><p id="p0065" class="elsevierStylePara elsevierViewall">Using oil red staining we observed that untreated Huh7&#46;5 cells revealed almost absence of intracellular lipid &#40;<a class="elsevierStyleCrossRef" href="#f0005">Figure 1</a>A&#41;&#46; However&#44; as shown in <a class="elsevierStyleCrossRef" href="#f0005">figure 1</a>B&#44; after OA exposure LD were higher in number and size&#46;</p><elsevierMultimedia ident="f0005"></elsevierMultimedia><p id="p0070" class="elsevierStylePara elsevierViewall">Using a fluorescence-based AdipoRed<span class="elsevierStyleSup">TM</span> assay&#44; the amount of intracellular lipids increased in the presence of OA 78&#46;31 &#177; 3&#46;78&#37; compared to untreated cells &#40;<a class="elsevierStyleCrossRef" href="#f0005">Figure 1</a>&#1057;&#41;&#46;</p></span><span id="s0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0075">Effects of Quercetin and water-soluble extracts from mushroom and artichoke on hepatic lipid accumulation</span><p id="p0075" class="elsevierStylePara elsevierViewall">First&#44; we have determined the dose by cytotoxic assay and at 0&#46;1 mg&#47;mL no toxic effects were observed &#40;data not shown&#41;&#46; A significant reduction in lipid accumulation was observed by microscopy after quercetin or extracts addition &#40;<a class="elsevierStyleCrossRef" href="#f0010">Figure 2</a>A&#41;&#46; After treatment&#44; a significant reduction of the LD size in OA-treated cells was found &#40;<a class="elsevierStyleCrossRef" href="#f0010">Figure 2</a>B&#41;&#46; Intracellular lipid concentration was decreased in OA-treated cells by quercetin &#40;66 &#177; 2&#46;04&#37;&#41;&#44; M aqueous extract &#40;20&#46;40 &#177; 3&#46;63&#37;&#41; and A aqueous extract &#40;24&#46;61&#177; 0&#46;19&#37;&#41; &#40;<a class="elsevierStyleCrossRef" href="#f0010">Figure 2</a>C&#41;&#46;</p><elsevierMultimedia ident="f0010"></elsevierMultimedia></span><span id="s0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0080">Aqueous extracts modulated lipogenesis-related gene expression</span><p id="p0080" class="elsevierStylePara elsevierViewall">Genes involved in lipogenesis <span class="elsevierStyleItalic">&#40;SREBP-1c</span>&#44; PPAR&#947; and PPAR&#945;&#41;&#44; significantly increased in OA-induced Huh7&#46;5 cells at the mRNA levels &#40;p &#60; 0&#46;05&#41; &#40;<a class="elsevierStyleCrossRef" href="#f0015">Figure 3</a>&#41;&#46; As shown in <a class="elsevierStyleCrossRef" href="#f0015">figure 3</a>A&#44; quercetin treatment decreased the expression of <span class="elsevierStyleItalic">SREBP-1c</span> &#40;fold inhibition&#58; 1&#46;57 &#177; 0&#46;13&#41; and PPARy &#40;fold inhibition&#58; 0&#46;77 &#177; 0&#46;10&#41;&#46; The same effect was observed after treatment with the aqueous-extracts&#46; Conversely&#44; quercetin and artichoke extract increased the gene expression of <span class="elsevierStyleItalic">PPAR</span>&#945; &#40;<a class="elsevierStyleCrossRef" href="#f0015">Figure 3</a>A&#41;&#46; <span class="elsevierStyleItalic">ACAT</span> gene expression was increased by OA 1mM and decreased significantly &#40;fold inhibition&#58; 1&#46;48 &#177; 0&#46;3&#41; after quercetin treatment being this reduction less significantly after extract addition &#40;<a class="elsevierStyleCrossRef" href="#f0015">Figure 3</a>B&#41;&#46; Genes implicated on triglycerides and VLDL pathways were also modulated in OA-induced Huh7&#46;5 cells&#46; <span class="elsevierStyleItalic">DGAT-l</span> and <span class="elsevierStyleItalic">APOE</span> mRNA levels were significantly increased and <span class="elsevierStyleItalic">MTTP</span> and <span class="elsevierStyleItalic">APOB</span> were decreased in OA-induced Huh7&#46;5 cells &#40;p &#62; 0&#46;05&#41;&#46; Quercetin and artichoke extract decreased DGAT1 mRNA levels in Huh7&#46;5 and the apolipoproteins genes were repressed by quercetin in the OA-induced model &#40;<a class="elsevierStyleCrossRef" href="#f0005">Figure 1</a>D&#41;&#46;</p><elsevierMultimedia ident="f0015"></elsevierMultimedia></span></span><span id="s0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0085">Discussion</span><p id="p0085" class="elsevierStylePara elsevierViewall">Current NAFLD therapies include lifestyle modifications&#44; physical activity and medical intervention&#46; Probiotics&#44; functional food and several natural compounds &#40;i&#46;e&#46; resveratrol and quercetin&#44;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> anthocyanins&#44;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> vitamin E<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a>&#41; may be promising in helping therapeutic approaches&#46; On the basis of these data&#44; it seems that foods rich in quercetin and&#47;or including natural extracts from mushroom and artichoke may be useful for the prevention of NAFLD&#46;</p><p id="p0090" class="elsevierStylePara elsevierViewall">In addition to resveratrol and quercetin&#44; other polyphenols such as Anthocyanin Cy-3-g&#44; Proanthocyanidins&#44; Theaflavin &#40;a flavan-3-ol&#41; and Ellagic acid have been studied as potential agent for both prevention and treatment of hepatic steatosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">28</span></a>&#8211;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> Resveratrol is a stilbene occurring naturally in several plants and provided in the diet by various foodstuffs&#46; In recent years&#44; it has been shown to modify lipid metabolism&#44; and more specifically to induce a reduction in liver triacylglycerol content&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32</span></a>&#8211;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a></p><p id="p0095" class="elsevierStylePara elsevierViewall">Quercetin is a natural polyphenol belonging to a group with a variable structure&#44; known as flavonoids&#46; It is found in onions&#44; broccoli&#44; tomatoes&#44; apples and berries&#46; Several studies have shown that quercetin has more than one effect in order to modify the intracellular lipid content&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> Vidyashankar and colleagues<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> showed that quercetin decreased triacylglycerol accumulation&#44; modulated the insulin resistance&#44; inflammatory cytokine secretion&#44; and increased cellular antioxidants suggesting that quercetin could be an effective molecule for NAFLD&#46;</p><p id="p0100" class="elsevierStylePara elsevierViewall">In this study&#44; we have shown that aqueous extracts from mushroom and artichoke may be useful for therapeutic interventions in lipid accumulation-related liver pathologies like NAFLD&#46; Beneficial effects of polyphenols in the prevention and treatment of liver steatosis have been widely reported&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> These molecules present hepaticprotective effects because they reduce liver fat accumulation&#44; mainly by lowering lipogenesis and increasing fatty acid oxidation&#46; Besides&#44; it has been shown that polyphenols are able to reduce oxidative stress and inflammation&#44; the main factors responsible for liver damage&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> To date&#44; these beneficial effects have been demonstrated in cultured cells and animal models&#46;</p><p id="p0105" class="elsevierStylePara elsevierViewall">Quercetin was used as a reference or like a positive control&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> Our results confirm that quercetin reduces TGs concentration and LDs size in an OA <span class="elsevierStyleItalic">in vitro</span> model&#46; The use of aqueous extracts showed similar effects than quercetin such as an important reduction of intracellular lipid content&#44; LD size and intracellular triglycerides concentration&#46;</p><p id="p0110" class="elsevierStylePara elsevierViewall">Lipid accumulation in the liver may be caused by enhanced de novo lipogenesis&#44; activation of lipid uptake&#44; and lowering of lipid catabolism&#46; Fatty acids are known to be ligands for nuclear transcription factors&#44; such as <span class="elsevierStyleItalic">SREBP-1c&#44; PPAR&#947;</span> and <span class="elsevierStyleItalic">PPAR&#945;&#46;</span><a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> It has been reported that PPAR&#945; knockout &#40;-&#47;-&#41; mice developed severe hepatic steatosis upon fasting as a result of failure to up-regulate the fatty acid oxidation pathway&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a><span class="elsevierStyleItalic">PPAR</span>&#945; activation is required to enhance hepatic lipid turnover to enable sufficient clearance of lipids from the liver&#44; preventing lipid accumulation and peroxidation in murine NASH models&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> Our result confirmed that the therapeutic effect of quercetin on lipid metabolism in Huh7&#46;5-induced fatty liver cells is partly due to <span class="elsevierStyleItalic">PPAR&#945;</span> upregulation &#40;inducing lipolysis&#41; and <span class="elsevierStyleItalic">SREBP-1c</span> downregulation &#40;reducing lipogenesis&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a><span class="elsevierStyleItalic">Cynara scolymus</span> extract increased <span class="elsevierStyleItalic">PPAR&#945;</span> gene expression levels in the model of steatosis which controls fatty acid degradation&#46; Anderson&#44; <span class="elsevierStyleItalic">et al&#46;</span> showed that pathogenesis of NASH increased the pool of free fatty acids through de novo lipid synthesis and nuclear receptors activation <span class="elsevierStyleItalic">&#40;SREBP-1&#44; ChREBP-1</span>&#44; and PPAR&#947;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> In our study&#44; OA significantly increased <span class="elsevierStyleItalic">SREPB-lc</span> gene expression which was disrupted by quercetin&#46; In addition&#44; <span class="elsevierStyleItalic">PPAR</span>&#947; gene expression was induced by OA and this effect was diminished after treatment&#46; Beside&#44; we demonstrated that OA modified genes involved in TGs synthesis and VLDL secretion pathway however quercetin and aqueous extracts treatment did not affect on their expression&#46; This work demonstrated that <span class="elsevierStyleItalic">Agaricus bisporus</span> and <span class="elsevierStyleItalic">Cynara scolymus</span> aqueous extracts&#44; together with quercetin treatment&#44; modified nuclear transcription factors leading to a significant decrease of intracellular lipid content and LDs size&#46;</p><p id="p0115" class="elsevierStylePara elsevierViewall">In conclusion&#44; these compounds may interfere and prevent the development of NAFLD in the presence of unfavourable genotype GG of <span class="elsevierStyleItalic">PNPLA3&#46;</span> Quercetin and the aqueous extracts &#40;A and M&#41; may prevent the progression of liver damage related to NAFLD by two independent mechanisms&#58; inhibition of lipogenesis by reducing <span class="elsevierStyleItalic">SREBP-lc</span> and promoting lipolysis through <span class="elsevierStyleItalic">PPAR&#945;</span> induction &#40;<a class="elsevierStyleCrossRef" href="#f0020">Figure 4</a>&#41;&#46; Further studies are required to clarify the molecular mechanism including their role in the oxidative stress&#46; In addition&#44; it would be needed to test the specific effect of single compounds which are included in the aqueous extracts described in this work&#46;</p><elsevierMultimedia ident="f0020"></elsevierMultimedia></span><span id="s0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0090">Abbreviations</span><p id="p0120" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="l0005"><li class="elsevierStyleListItem" id="u0005"><span class="elsevierStyleLabel">&#8226;</span><p id="p0125" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">A&#58;</span> Cynara scolymus&#46;</p></li><li class="elsevierStyleListItem" id="u0010"><span class="elsevierStyleLabel">&#8226;</span><p id="p0130" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">AbAE&#58;</span> Agaricus bisporus aqueous extract&#46;</p></li><li class="elsevierStyleListItem" id="u0015"><span class="elsevierStyleLabel">&#8226;</span><p id="p0135" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">ACAT&#58;</span> Cholesterol acyltransferase&#46;</p></li><li class="elsevierStyleListItem" id="u0020"><span class="elsevierStyleLabel">&#8226;</span><p id="p0140" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">APOB&#58;</span> Apolipoprotein-B&#46;</p></li><li class="elsevierStyleListItem" id="u0025"><span class="elsevierStyleLabel">&#8226;</span><p id="p0145" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">APOE&#58;</span> Apolipoprotein-E&#46;</p></li><li class="elsevierStyleListItem" id="u0030"><span class="elsevierStyleLabel">&#8226;</span><p id="p0150" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">DAPI&#58;</span> 46-diamidino- 2-phenylindole&#46;</p></li><li class="elsevierStyleListItem" id="u0035"><span class="elsevierStyleLabel">&#8226;</span><p id="p0155" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">DGAT-1&#58;</span> Diacylglycerol acyltransferase-1&#46;</p></li><li class="elsevierStyleListItem" id="u0040"><span class="elsevierStyleLabel">&#8226;</span><p id="p0160" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">DGAT-2&#58;</span> Diacylglycerol acyltransferase-2&#46;</p></li><li class="elsevierStyleListItem" id="u0045"><span class="elsevierStyleLabel">&#8226;</span><p id="p0165" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">DMEM&#58;</span> Dulbecco&#8217;s Modified Eagle&#8217;s Medium&#46;</p></li><li class="elsevierStyleListItem" id="u0050"><span class="elsevierStyleLabel">&#8226;</span><p id="p0170" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">DMSO&#58;</span> Dimethyl sulfoxide&#46;</p></li><li class="elsevierStyleListItem" id="u0055"><span class="elsevierStyleLabel">&#8226;</span><p id="p0175" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">FASN&#58;</span> Fatty Acid Synthase&#46;</p></li><li class="elsevierStyleListItem" id="u0060"><span class="elsevierStyleLabel">&#8226;</span><p id="p0180" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">FBS&#58;</span> Fetal bovine serum&#46;</p></li><li class="elsevierStyleListItem" id="u0065"><span class="elsevierStyleLabel">&#8226;</span><p id="p0185" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">FFA&#58;</span> Free fatty acid&#46;</p></li><li class="elsevierStyleListItem" id="u0070"><span class="elsevierStyleLabel">&#8226;</span><p id="p0190" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">FITC&#58;</span> Fluorescein isothiocyanate&#46;</p></li><li class="elsevierStyleListItem" id="u0075"><span class="elsevierStyleLabel">&#8226;</span><p id="p0195" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">LDs&#58;</span> Lipid droplets&#46;</p></li><li class="elsevierStyleListItem" id="u0080"><span class="elsevierStyleLabel">&#8226;</span><p id="p0200" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">M&#58;</span> Agaricus Bisporus&#46;</p></li><li class="elsevierStyleListItem" id="u0085"><span class="elsevierStyleLabel">&#8226;</span><p id="p0205" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">MTTP&#58;</span> Microsomal triglyceride transfer protein&#46;</p></li><li class="elsevierStyleListItem" id="u0090"><span class="elsevierStyleLabel">&#8226;</span><p id="p0210" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">NAFLD&#58;</span> Non-alcoholic fatty liver disease&#44;</p></li><li class="elsevierStyleListItem" id="u0095"><span class="elsevierStyleLabel">&#8226;</span><p id="p0215" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">NASH&#58;</span> Non-alcoholic steatohepatitis&#46;</p></li><li class="elsevierStyleListItem" id="u0100"><span class="elsevierStyleLabel">&#8226;</span><p id="p0220" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">OA&#58;</span> Oleic acid&#46;</p></li><li class="elsevierStyleListItem" id="u0105"><span class="elsevierStyleLabel">&#8226;</span><p id="p0225" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">ORO&#58;</span> Oil Red O&#46;</p></li><li class="elsevierStyleListItem" id="u0110"><span class="elsevierStyleLabel">&#8226;</span><p id="p0230" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">PBS&#58;</span> Phosphate-buffered saline&#46;</p></li><li class="elsevierStyleListItem" id="u0115"><span class="elsevierStyleLabel">&#8226;</span><p id="p0235" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">PNPLA3&#58;</span> Patatin-like phospholipase domain-containing protein 3&#46;</p></li><li class="elsevierStyleListItem" id="u0120"><span class="elsevierStyleLabel">&#8226;</span><p id="p0240" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">PPAR-a&#58;</span> Peroxisome proliferator-activated receptor alpha&#46;</p></li><li class="elsevierStyleListItem" id="u0125"><span class="elsevierStyleLabel">&#8226;</span><p id="p0245" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">PPAR-&#63;&#58;</span> Peroxisome proliferator-activated receptor gamma&#46;</p></li><li class="elsevierStyleListItem" id="u0130"><span class="elsevierStyleLabel">&#8226;</span><p id="p0250" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">q-PCR&#58;</span> Quantitative polymerase chain reaction&#46;</p></li><li class="elsevierStyleListItem" id="u0135"><span class="elsevierStyleLabel">&#8226;</span><p id="p0255" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">RT&#58;</span> Retro-transcription&#46;</p></li><li class="elsevierStyleListItem" id="u0140"><span class="elsevierStyleLabel">&#8226;</span><p id="p0260" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">SD&#58;</span> Standard deviation&#46;</p></li><li class="elsevierStyleListItem" id="u0145"><span class="elsevierStyleLabel">&#8226;</span><p id="p0265" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">SREBP&#58;</span> Sterol regulatory element binding protein-1&#46;</p></li><li class="elsevierStyleListItem" id="u0150"><span class="elsevierStyleLabel">&#8226;</span><p id="p0270" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">TG&#58;</span> Triglycerides&#46;</p></li></ul></p></span><span id="s0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0095">No Financial Disclose</span><p id="p0275" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="l0010"><li class="elsevierStyleListItem" id="u0155"><span class="elsevierStyleLabel">&#8226;</span><p id="p0280" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Financial support&#46;</span> None&#46;</p></li></ul></p></span><span id="s0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0100">Potential Competing Interest</span><p id="p0285" class="elsevierStylePara elsevierViewall">None&#46;</p></span><span id="s0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0105">Specific Author Contribution</span><p id="p0290" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="l0015"><li class="elsevierStyleListItem" id="u0160"><span class="elsevierStyleLabel">&#8226;</span><p id="p0295" class="elsevierStylePara elsevierViewall">Planning and conducting the study&#58; &#193;ngela Rojas&#44; Manuel Romero-G&#243;mez&#46;</p></li><li class="elsevierStyleListItem" id="u0165"><span class="elsevierStyleLabel">&#8226;</span><p id="p0300" class="elsevierStylePara elsevierViewall">Drafting the manuscript&#58; &#193;ngela Rojas&#44; Jose Antonio del Campo&#44; Manuel Romero-Gomez&#46;</p></li><li class="elsevierStyleListItem" id="u0170"><span class="elsevierStyleLabel">&#8226;</span><p id="p0305" class="elsevierStylePara elsevierViewall">Interpreting data&#58; Jose Antonio del Campo&#44; Juan Bautista&#44; Manuel Romero-Gomez&#46;</p></li><li class="elsevierStyleListItem" id="u0175"><span class="elsevierStyleLabel">&#8226;</span><p id="p0310" class="elsevierStylePara elsevierViewall">Performing <span class="elsevierStyleItalic">in vitro</span> studies&#58; &#193;ngela Rojas&#44; Paloma Gallego&#44; Antonio Gil-G&#243;mez&#44; Roc&#237;o Mu&#241;oz&#44; Lourdes Rojas&#44; Rosario Maldonado&#44; Roc&#237;o Gallego-Dur&#225;n&#44; Marta Garc&#237;a-Valdecasas&#46;</p></li></ul></p></span></span>"
    "textoCompletoSecciones" => array:1 [
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        0 => array:3 [
          "identificador" => "xres1190046"
          "titulo" => "Abstract"
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            0 => array:1 [
              "identificador" => "abs0010"
            ]
          ]
        ]
        1 => array:2 [
          "identificador" => "xpalclavsec1109524"
          "titulo" => "Keywords"
        ]
        2 => array:2 [
          "identificador" => "s0005"
          "titulo" => "Introduction"
        ]
        3 => array:3 [
          "identificador" => "s0010"
          "titulo" => "Material and Methods"
          "secciones" => array:6 [
            0 => array:3 [
              "identificador" => "s0015"
              "titulo" => "Cell Culture"
              "secciones" => array:1 [
                0 => array:2 [
                  "identificador" => "s0020"
                  "titulo" => "PNPLA3 genotyping"
                ]
              ]
            ]
            1 => array:2 [
              "identificador" => "s0025"
              "titulo" => "Preparation of aqueous extracts"
            ]
            2 => array:2 [
              "identificador" => "s0030"
              "titulo" => "Detection of LDs by Fluorescent Microscopy Oil Red O &#40;ORO&#41; cell staining&#46;"
            ]
            3 => array:2 [
              "identificador" => "s0035"
              "titulo" => "Fluorimetric determination of intracellular fat content - Nile red staining"
            ]
            4 => array:2 [
              "identificador" => "s0040"
              "titulo" => "RNA isolation&#44; retro-transcription and quantitative polymerase chain reaction &#40;q-PCR&#41;"
            ]
            5 => array:2 [
              "identificador" => "s0045"
              "titulo" => "Statistical Analysis"
            ]
          ]
        ]
        4 => array:3 [
          "identificador" => "s0050"
          "titulo" => "Results"
          "secciones" => array:4 [
            0 => array:2 [
              "identificador" => "s0055"
              "titulo" => "Huh7&#46;5 PNPLA3 genotype"
            ]
            1 => array:2 [
              "identificador" => "s0060"
              "titulo" => "Oleic acid-induced intracellular lipid accumulation in Huh7&#46;5 cells"
            ]
            2 => array:2 [
              "identificador" => "s0065"
              "titulo" => "Effects of Quercetin and water-soluble extracts from mushroom and artichoke on hepatic lipid accumulation"
            ]
            3 => array:2 [
              "identificador" => "s0070"
              "titulo" => "Aqueous extracts modulated lipogenesis-related gene expression"
            ]
          ]
        ]
        5 => array:2 [
          "identificador" => "s0075"
          "titulo" => "Discussion"
        ]
        6 => array:2 [
          "identificador" => "s0080"
          "titulo" => "Abbreviations"
        ]
        7 => array:2 [
          "identificador" => "s0085"
          "titulo" => "No Financial Disclose"
        ]
        8 => array:2 [
          "identificador" => "s0090"
          "titulo" => "Potential Competing Interest"
        ]
        9 => array:2 [
          "identificador" => "s0095"
          "titulo" => "Specific Author Contribution"
        ]
        10 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
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    "fechaRecibido" => "2017-05-13"
    "fechaAceptado" => "2017-06-27"
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1109524"
          "palabras" => array:8 [
            0 => "Steatosis"
            1 => "Lipid droplets"
            2 => "Triglycerides"
            3 => "Quercetin"
            4 => "<span class="elsevierStyleItalic">Cynara scolymus</span>"
            5 => "<span class="elsevierStyleItalic">Agaricus Bisporus</span>"
            6 => "Mushroom"
            7 => "Artichoke"
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    "resumen" => array:1 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abs0010" class="elsevierStyleSection elsevierViewall"><p id="sp0025" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Background &#38; aims&#46;</span> G-allele of <span class="elsevierStyleItalic">PNPLA3</span> &#40;rs738409&#41; favours triglycerides accumulation and steatosis&#46; In this study&#44; we examined the effect of quercetin and natural extracts from mushroom and artichoke on reducing lipid accumulation in hepatic cells&#46;</p><p id="sp0030" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Material and methods&#46;</span> Huh7&#46;5 cells were exposed to oleic acid &#40;OA&#41; and treated with quercetin and extracts to observe the lipid accumulation&#44; the intracellular-TG concentration and the LD size&#46; Sterol regulatory element binding proteins-1 <span class="elsevierStyleItalic">&#40;SREBP-1&#41;</span>&#44; peroxisome proliferator-activated receptor &#40;PPAR&#945;-&#947;&#41; and cholesterol acyltransferase &#40;ACAT&#41; gene expression levels were analysed&#46;</p><p id="sp0035" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Results&#46;</span> Quercetin decreased the intracellular lipids&#44; LD size and the levels of intracellular-TG through the down-regulation of <span class="elsevierStyleItalic">SREBP-1c&#44; PPAR&#947;and ACAT1</span> increasing <span class="elsevierStyleItalic">PPAR&#945;&#46;</span> The natural-extracts suppressed OA-induced lipid accumulation and the intracellular-TG&#46; They down-regulate the hepatic lipogenesis through <span class="elsevierStyleItalic">SREBP-1c</span>&#44; besides the activation of lipolysis through the increasing of <span class="elsevierStyleItalic">PPAR&#945;</span> expression&#46;</p><p id="sp0040" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Conclusions&#46;</span> Quercetin and the aqueous extracts decrease intracellular lipid accumulation by down-regulation of lipogenesis and up-regulation of lipolysis&#46;</p></span>"
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          "en" => "<p id="sp0005" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Untreated Huh7&#46;5 <span class="elsevierStyleBold">&#40;A&#41;</span> and Huh7&#46;5 cells cultured at OA concentrations 1 mM&#44; for 48 hours <span class="elsevierStyleBold">&#40;B&#41;&#46;</span> LDs and nuclei were stained with ORO &#40;red&#41; and Dapi &#40;blue&#41;&#44; respectively&#46; Images were acquired with a fluorescence microscope &#40;OLIMPUS BX41&#41; equipped with the standard epifluorescence filter set up for DAPI and FITC under oil with a 100x plan apochromat objective&#46; <span class="elsevierStyleBold">C&#46;</span> Intracellular triglycerides concentration&#46; AdipoRed&#8482; Assay of Huh7&#46;5 and OA-Huh7&#46;5 cells&#46; The intracellular triglycerides were stained and the concentration of triglycerides was quantified by fluorescence&#46; &#40;Huh7&#46;5 fold&#61;1&#41; &#40;&#42;&#42;&#42;p &#60; 0&#46;01&#41;&#46; Data are presented as the mean values &#177; SD obtained from three independent experiments&#46; <span class="elsevierStyleBold">D&#46; &#40;A&#41;</span> mRNA gene expression levels of</span> DGAT-1&#44; DGAT-2&#44; MTTP&#44; FASN&#44; apoE <span class="elsevierStyleItalic">and</span> apoB <span class="elsevierStyleItalic">were determined by RT-PCR&#46; Results were normalized using</span> GAPDH <span class="elsevierStyleItalic">and Huh7&#46;5 non-treated cells were used as reference&#46; &#42;p &#60; 0&#46;05&#59; &#42;&#42;p &#60; 0&#46;01 and &#42;&#42;&#42;p &#60; 0&#46;001&#46; Data are the mean value &#177; SD obtained from three independent experiments&#46;</span></p>"
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          "en" => "<p id="sp0010" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold"><span class="elsevierStyleItalic">A&#46;</span></span> Huh7&#46;5 &#40;a&#41; and OA-Huh7&#46;5 &#40;e&#41; cells treated with quercetin 50 &#181;&#1052; &#40;b-f&#41;&#44; aqueous extracts from mushroom &#40;M&#41; &#40;c-g&#41; and artichoke &#40;A&#41; &#40;d-h&#41; &#40;0&#46;1 mg&#47;mL&#41;&#44; for 48 h&#46; LDs and nuclei were stained with ORO &#40;red&#41; and Dapi &#40;blue&#41;&#44; respectively&#46; Images were taken using a fluorescence microscope &#40;OLIMPUS BX41&#41; equipped with a 100x objective and the standard epifluorescence filter set up for DAPI and FITC&#46; <span class="elsevierStyleBold">B&#46;</span> LDs size were measured by Imaging Software cell&#94;F Software&#46; Results are expressed as fold-area &#181;m<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>&#46; <span class="elsevierStyleBold">C&#46;</span> Intracellular triglycerides concentration&#46; AdipoRed Assay&#46; The intracellular triglycerides were stained and the concentration of triglycerides was quantifed by fluorescence &#40;Huh7&#46;5 fold &#61; 1&#41;&#46; Data are presented as the mean values &#177; SD obtained from three independent experiments&#46; Experiments were performed in triplicate&#46; &#40;&#42;&#41; p &#60; 0&#46;05&#59; &#40;&#42;&#42;&#41; p &#60; 0&#46;01 &#40;&#42;&#42;&#42;&#41; p &#60; 0&#46;001&#46;</p>"
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          "en" => "<p id="sp0015" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold"><span class="elsevierStyleItalic">A&#46;</span></span><span class="elsevierStyleItalic">mRNA gene expression levels of</span> SREBP-1c&#44; PPAR<span class="elsevierStyleItalic">&#947;</span><span class="elsevierStyleItalic">and</span> PPAR<span class="elsevierStyleItalic">&#945;</span><span class="elsevierStyleItalic">were determined by RT-PCR&#46; B&#46;</span> ACAT-1 <span class="elsevierStyleItalic">mRNA gene expresision levels&#46; Results were normalized using</span> GAPDH <span class="elsevierStyleItalic">and Huh7&#46;5 non-treated cells were used as reference&#46; &#42;p &#60; 0&#46;05&#59; &#42;&#42;p &#60; 0&#46;01 and &#42;&#42;&#42;p &#60; 0&#46;001&#46; Data are the mean value &#177; SD obtained from three independent experiments&#46;</span></p>"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Non-alcoholic fatty liver disease 2015"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "Ahmed M&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "World J Hepatol"
                        "fecha" => "2015"
                        "volumen" => "18"
                        "paginaInicial" => "1450"
                        "paginaFinal" => "1459"
                      ]
                    ]
                  ]
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                    0 => array:2 [
                      "titulo" => "Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance&#58; lessons from genetically engineered mice"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "Postic C&#46;"
                            1 => "Girard J&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1172/JCI34275"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Invest"
                        "fecha" => "2008"
                        "volumen" => "118"
                        "paginaInicial" => "829"
                        "paginaFinal" => "838"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18317565"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0015"
              "etiqueta" => "3&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Interrelationship between fatty liver and insulin resistance in the development of type 2 diabetes"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "Sung K&#46;C&#46;"
                            1 => "Kim S&#46;H&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1210/jc.2010-2190"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Endocrinol Metab"
                        "fecha" => "2011"
                        "volumen" => "96"
                        "paginaInicial" => "1093"
                        "paginaFinal" => "1097"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21252243"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0020"
              "etiqueta" => "4&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The histologic spectrum of nonalcoholic fatty liver disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "Contos M&#46;J&#46;"
                            1 => "Choudhury J&#46;"
                            2 => "Mills A&#46;S&#46;"
                            3 => "Sanyal A&#46;J&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.cld.2004.04.013"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Liver Dis"
                        "fecha" => "2004"
                        "volumen" => "8"
                        "paginaInicial" => "481"
                        "paginaFinal" => "500"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15331059"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0025"
              "etiqueta" => "5&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Human fatty liver disease&#58; old questions and new insights"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "Cohen J&#46;C&#46;"
                            1 => "Horton J&#46;D&#46;"
                            2 => "Hobbs H&#46;H&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1126/science.1204265"
                      "Revista" => array:6 [
                        "tituloSerie" => "Science"
                        "fecha" => "2011"
                        "volumen" => "332"
                        "paginaInicial" => "1519"
                        "paginaFinal" => "1523"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21700865"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0030"
              "etiqueta" => "6&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Recent insights into hepatic lipid metabolism in non-alcoholic fatty liver disease &#40;NAFLD&#41;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "Musso G&#46;"
                            1 => "Gambino R&#46;"
                            2 => "Cassader M&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.plipres.2008.08.001"
                      "Revista" => array:6 [
                        "tituloSerie" => "Prog Lipid Res"
                        "fecha" => "2009"
                        "volumen" => "48"
                        "paginaInicial" => "1"
                        "paginaFinal" => "26"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18824034"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0035"
              "etiqueta" => "7&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Inhibition of ceramide de novo synthesis reduces liver lipid accumulation in rats with nonalcoholic fatty liver disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Kurek K&#46;"
                            1 => "Piotrowska D&#46;M&#46;"
                            2 => "Wiesiolek-Kurek P&#46;"
                            3 => "Lukaszuk B&#46;"
                            4 => "Chabowski A&#46;"
                            5 => "G&#243;rski J&#46;"
                            6 => "Zendzian-Piotrowska M&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/liv.12331"
                      "Revista" => array:6 [
                        "tituloSerie" => "Liver Int"
                        "fecha" => "2014"
                        "volumen" => "34"
                        "paginaInicial" => "1074"
                        "paginaFinal" => "1083"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24106929"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib0040"
              "etiqueta" => "8&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Inhibitory effect of blueberry polyphenolic compounds on oleic acid-induced hepatic steatosis in vitro"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:7 [
                            0 => "Liu Y&#46;"
                            1 => "Wang D&#46;"
                            2 => "Zhang D&#46;"
                            3 => "Lv Y&#46;"
                            4 => "Wei Y&#46;"
                            5 => "Wu W&#46;"
                            6 => "Zhou F&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "J Agric Food Chem"
                        "fecha" => "2011"
                        "volumen" => "23"
                        "paginaInicial" => "12254"
                        "paginaFinal" => "12263"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib0045"
              "etiqueta" => "9&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Curcumin decreases oleic acid-induced lipid accumulation via AMPK phosphorylation in hepatocarcinoma cells"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:7 [
                            0 => "Kang O&#46;H&#46;"
                            1 => "Kim S&#46;B&#46;"
                            2 => "Seo Y&#46;S&#46;"
                            3 => "Joung D&#46;K&#46;"
                            4 => "Mun S&#46;H&#46;"
                            5 => "Choi J&#46;G&#46;"
                            6 => "Lee Y&#46;M&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur Rev Med Pharmacol Sci"
                        "fecha" => "2013"
                        "volumen" => "17"
                        "paginaInicial" => "2578"
                        "paginaFinal" => "2586"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24142602"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib0050"
              "etiqueta" => "10&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pinus densiflora Sieb&#46; et Zucc&#46; alleviates lipogenesis and oxidative stress during oleic acid-induced steatosis in HepG2 cells"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "Hwang Y&#46;J&#46;"
                            1 => "Wi H&#46;R&#46;"
                            2 => "Kim H&#46;R&#46;"
                            3 => "Park K&#46;W&#46;"
                            4 => "Hwang K&#46;A&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3390/nu6072956"
                      "Revista" => array:6 [
                        "tituloSerie" => "Nutrients"
                        "fecha" => "2014"
                        "volumen" => "6"
                        "paginaInicial" => "2956"
                        "paginaFinal" => "2972"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25057104"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib0055"
              "etiqueta" => "11&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Quercetin improves insulin resistance and hepatic lipid accumulation in vitro in a NAFLD cell model"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:7 [
                            0 => "Li X&#46;"
                            1 => "Wang R&#46;"
                            2 => "Zhou N&#46;"
                            3 => "Wang X&#46;"
                            4 => "Liu Q&#46;"
                            5 => "Bai Y&#46;"
                            6 => "Liu Z&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3892/br.2012.27"
                      "Revista" => array:6 [
                        "tituloSerie" => "Biomed Rep"
                        "fecha" => "2013"
                        "volumen" => "1"
                        "paginaInicial" => "71"
                        "paginaFinal" => "76"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24648896"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib0060"
              "etiqueta" => "12&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Meta-analysis of traditional herbal medicine in the treatment of nonalcoholic fatty liver disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "Peng H&#46;"
                            1 => "He Y&#46;"
                            2 => "Zheng G&#46;"
                            3 => "Zhang W&#46;"
                            4 => "Yao Z&#46;"
                            5 => "Xie W&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Cell Mol Biol"
                        "fecha" => "2016"
                        "volumen" => "62"
                        "paginaInicial" => "88"
                        "paginaFinal" => "95"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27188741"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib0065"
              "etiqueta" => "13&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Natural antioxidants for non-alcoholic fatty liver disease&#58; molecular targets and clinical perspectives"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "Salomone F&#46;"
                            1 => "Godos J&#46;"
                            2 => "Zelber-Sagi S&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/liv.13035"
                      "Revista" => array:6 [
                        "tituloSerie" => "Liver Int"
                        "fecha" => "2016"
                        "volumen" => "36"
                        "paginaInicial" => "5"
                        "paginaFinal" => "20"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26725890"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib0070"
              "etiqueta" => "14&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The genetics of NAFLD"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "Anstee Q&#46;M&#46;"
                            1 => "Day C&#46;P&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/nrgastro.2013.182"
                      "Revista" => array:6 [
                        "tituloSerie" => "Nat Rev Gastroenterol Hepatol"
                        "fecha" => "2013"
                        "volumen" => "10"
                        "paginaInicial" => "645"
                        "paginaFinal" => "655"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24061205"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib0075"
              "etiqueta" => "15&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:7 [
                            0 => "Romeo S&#46;"
                            1 => "Kozlitina J&#46;"
                            2 => "Xing C&#46;"
                            3 => "Pertsemlidis A&#46;"
                            4 => "Cox D&#46;"
                            5 => "Pennacchio L&#46;A&#46;"
                            6 => "Boerwinkle E&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/ng.257"
                      "Revista" => array:6 [
                        "tituloSerie" => "Nat Genet"
                        "fecha" => "2008"
                        "volumen" => "40"
                        "paginaInicial" => "1461"
                        "paginaFinal" => "1465"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18820647"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib0080"
              "etiqueta" => "16&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A sequence variation &#40;I148M&#41; in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:7 [
                            0 => "He S&#46;"
                            1 => "McPhaul C&#46;"
                            2 => "Li J&#46;Z&#46;"
                            3 => "Garuti R&#46;"
                            4 => "Kinch L&#46;"
                            5 => "Grishin N&#46;V&#46;"
                            6 => "Cohen J&#46;C&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1074/jbc.M109.064501"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Biol Chem"
                        "fecha" => "2010"
                        "volumen" => "285"
                        "paginaInicial" => "6706"
                        "paginaFinal" => "6715"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20034933"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            16 => array:3 [
              "identificador" => "bib0085"
              "etiqueta" => "17&#46;"
              "referencia" => array:1 [
                0 => array:1 [
                  "referenciaCompleta" => "BasuRay S&#44; Smagris E&#44; Cohen JC&#44; Hobbs HH&#46; The PNPLA3 Variant Associated with Fatty Liver Disease &#40;I148M&#41; Accumulates on Lipid Droplets by Evading Ubiquitylation&#46; <span class="elsevierStyleItalic">Hepatology</span> 2017 &#91;Epub ahead of print&#93;&#46;"
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib0090"
              "etiqueta" => "18&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "PNPLA3 rs738409 causes steatosis according to viral &#38; IL28B genotypes in hepatitis C"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:7 [
                            0 => "Ampuero J&#46;"
                            1 => "Del Campo J&#46;A&#46;"
                            2 => "Rojas L&#46;"
                            3 => "Garc&#237;a-Lozano J&#46;R&#46;"
                            4 => "Sol&#225; R&#46;"
                            5 => "Andrade R&#46;"
                            6 => "Pons J&#46;A&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Ann Hepatol"
                        "fecha" => "2014"
                        "volumen" => "13"
                        "paginaInicial" => "356"
                        "paginaFinal" => "363"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24927606"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            18 => array:3 [
              "identificador" => "bib0095"
              "etiqueta" => "19&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effect of intracellular lipid accumulation in a new model of non-alcoholic fatty liver disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "Chavez-Tapia N&#46;C&#46;"
                            1 => "Rosso N&#46;"
                            2 => "Tiribelli C&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/1471-230X-12-20"
                      "Revista" => array:5 [
                        "tituloSerie" => "BMC Gastroenterol"
                        "fecha" => "2012"
                        "volumen" => "12"
                        "paginaInicial" => "20"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22380754"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            19 => array:3 [
              "identificador" => "bib0100"
              "etiqueta" => "20&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Preparation and Characterisation of Selenium-Enriched Mushroom Aqueous Enzymatic Extracts &#40;MAEE&#41; Obtained from the White Button Mushroom &#40;Agaricus bisporus&#41;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:7 [
                            0 => "Cremades O&#46;"
                            1 => "Diaz-Herrero M&#46;M&#46;"
                            2 => "Carbonero-Aguilar P&#46;"
                            3 => "Gutierrez-Gil J&#46;F&#46;"
                            4 => "Fontiveros E&#46;"
                            5 => "Rodr&#237;guez-Morgado B&#46;"
                            6 => "Parrado J&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Food Chemistry"
                        "fecha" => "2012"
                        "volumen" => "133"
                        "paginaInicial" => "1538"
                        "paginaFinal" => "1543"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            20 => array:3 [
              "identificador" => "bib0105"
              "etiqueta" => "21&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Inhibited proliferation of cyclooxygenase-2 expressing human hepatoma cells by NS-398 a selective COX-2 inhibitor"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "Hu K&#46;Q&#46;"
                            1 => "Yu C&#46;H&#46;"
                            2 => "Mineyama Y&#46;"
                            3 => "McCracken J&#46;D&#46;"
                            4 => "Hillebrand D&#46;J&#46;"
                            5 => "Hasan M&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Int J Oncol"
                        "fecha" => "2003"
                        "volumen" => "22"
                        "paginaInicial" => "757"
                        "paginaFinal" => "763"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12632065"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            21 => array:3 [
              "identificador" => "bib0110"
              "etiqueta" => "22&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Monocyte chemoattractant protein-1 secreted by adipose tissue induces direct lipid accumulation in hepatocytes"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:7 [
                            0 => "Clement S&#46;"
                            1 => "Juge-Aubry C&#46;"
                            2 => "Sgroi A&#46;"
                            3 => "Conzelmann S&#46;"
                            4 => "Pazienza V&#46;"
                            5 => "Pittet-Cuenod B&#46;"
                            6 => "Meier C&#46;A&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/hep.22404"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "2008"
                        "volumen" => "48"
                        "paginaInicial" => "799"
                        "paginaFinal" => "807"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18570214"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            22 => array:3 [
              "identificador" => "bib0115"
              "etiqueta" => "23&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Nile Red binding to HepG2 cells&#58; an improved assay for in vitro studies of hepatosteatosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:7 [
                            0 => "McMillian M&#46;K&#46;"
                            1 => "Grant E&#46;R&#46;"
                            2 => "Zhong Z&#46;"
                            3 => "Parker J&#46;B&#46;"
                            4 => "Li L&#46;"
                            5 => "Zivin R&#46;A&#46;"
                            6 => "Burczynski M&#46;E&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1089/109793301753407948"
                      "Revista" => array:7 [
                        "tituloSerie" => "In Vitr Mol Toxicol"
                        "fecha" => "2001"
                        "volumen" => "14"
                        "numero" => "3"
                        "paginaInicial" => "177"
                        "paginaFinal" => "190"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11846991"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            23 => array:3 [
              "identificador" => "bib0120"
              "etiqueta" => "24&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Single-step method of RNA isolation by acid guanidinium thiocyanate-phenolchloroform extraction"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "Chomczynski P&#46;"
                            1 => "Sacchi N&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1006/abio.1987.9999"
                      "Revista" => array:6 [
                        "tituloSerie" => "Anal Biochem"
                        "fecha" => "1987"
                        "volumen" => "162"
                        "paginaInicial" => "156"
                        "paginaFinal" => "159"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2440339"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            24 => array:3 [
              "identificador" => "bib0125"
              "etiqueta" => "25&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Flavonoids and Related Compounds in Non-Alcoholic Fatty Liver Disease Therapy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "Pisonero-Vaquero S&#46;"
                            1 => "Gonzalez-Gallego J&#46;"
                            2 => "Sanchez-Campos S&#46;"
                            3 => "Garcia-Mediavilla M&#46;V&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Curr Med Chem"
                        "fecha" => "2015"
                        "volumen" => "22"
                        "paginaInicial" => "2991"
                        "paginaFinal" => "3012"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26242257"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            25 => array:3 [
              "identificador" => "bib0130"
              "etiqueta" => "26&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A CONSORTcompliant randomized double-blind placebo-controlled pilot trial of purified anthocyanin in patients with nonalcoholic fatty liver disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "Zhang P&#46;W&#46;"
                            1 => "Chen F&#46;X&#46;"
                            2 => "Li D&#46;"
                            3 => "Ling W&#46;H&#46;"
                            4 => "Guo H&#46;H&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [
                        "tituloSerie" => "Medicine &#40;Baltimore&#41;"
                        "fecha" => "2015"
                        "volumen" => "94"
                        "paginaInicial" => "e758"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            26 => array:3 [
              "identificador" => "bib0135"
              "etiqueta" => "27&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Vitamin E therapy on aminotransferase levels in NAFLD&#47;NASH patients"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "Ji H&#46;F&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.nut.2015.02.010"
                      "Revista" => array:5 [
                        "tituloSerie" => "Nutrition"
                        "fecha" => "2015"
                        "volumen" => "31"
                        "paginaInicial" => "899"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25933502"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            27 => array:3 [
              "identificador" => "bib0140"
              "etiqueta" => "28&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Anthocyanin inhibits high glucose-induced hepatic mtGPAT1 activation and prevents fatty acid synthesis through PKC"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "Guo H&#46;"
                            1 => "Li D&#46;"
                            2 => "Ling W&#46;"
                            3 => "Feng X&#46;"
                            4 => "Xia M&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1194/jlr.M013375"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Lipid Res"
                        "fecha" => "2011"
                        "volumen" => "52"
                        "paginaInicial" => "908"
                        "paginaFinal" => "922"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21343633"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            28 => array:3 [
              "identificador" => "bib0145"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Grape seed proanthocyanidins repress the hepatic lipid regulators miR-33 and miR-122 in rats"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Baselga-Escudero L&#46;"
                            1 => "Blad&#233; C&#46;"
                            2 => "Ribas-Latre A&#46;"
                            3 => "Casanova E&#46;"
                            4 => "Salvad&#243; M&#46;J&#46;"
                            5 => "Arola L&#46;"
                            6 => "Arola-Arnal A&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/mnfr.201200237"
                      "Revista" => array:6 [
                        "tituloSerie" => "Mol Nutr Food Res"
                        "fecha" => "2012"
                        "volumen" => "56"
                        "paginaInicial" => "1636"
                        "paginaFinal" => "1646"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22965541"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            29 => array:3 [
              "identificador" => "bib0150"
              "etiqueta" => "30&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "HG&#46; 3-Caffeoyl 4-dihydrocaffeoylquinic acid from Salicornia herbacea attenuates high glucose-induced hepatic lipogenesis in human HepG2 cells through activation of the liver kinase B1 and silent information regulator T1&#47;AMPK-dependent pathway"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:7 [
                            0 => "PilHwang Y&#46;"
                            1 => "Gyun Kim H&#46;"
                            2 => "Choi J&#46;H&#46;"
                            3 => "Truong Do M&#46;"
                            4 => "Tran T&#46;P&#46;"
                            5 => "Chun H&#46;K&#46;"
                            6 => "Chung Y&#46;C&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/mnfr.201200529"
                      "Revista" => array:6 [
                        "tituloSerie" => "Mol Nutr Food Res"
                        "fecha" => "2013"
                        "volumen" => "57"
                        "paginaInicial" => "471"
                        "paginaFinal" => "482"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23349077"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            30 => array:3 [
              "identificador" => "bib0155"
              "etiqueta" => "31&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Ellagic acid improves hepatic steatosis and serum lipid composition through reduction of serum resistin levels and transcriptional activation of hepatic ppara in obese diabetic KK-A&#40;y&#41; mice"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "Yoshimura Y&#46;"
                            1 => "Nishii S&#46;"
                            2 => "Zaima N&#46;"
                            3 => "Moriyama T&#46;"
                            4 => "Kawamura Y&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.bbrc.2013.03.100"
                      "Revista" => array:6 [
                        "tituloSerie" => "Biochem Biophys Res Commun"
                        "fecha" => "2013"
                        "volumen" => "434"
                        "paginaInicial" => "486"
                        "paginaFinal" => "491"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23583377"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            31 => array:3 [
              "identificador" => "bib0160"
              "etiqueta" => "32&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Resveratrol inhibits fatty acid and triacylglycerol synthesis in rat hepatocytes"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "Gnoni G&#46;V&#46;"
                            1 => "Paglialonga G&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1365-2362.2008.02077.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur J Clin Invest"
                        "fecha" => "2009"
                        "volumen" => "39"
                        "paginaInicial" => "211"
                        "paginaFinal" => "218"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19260951"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            32 => array:3 [
              "identificador" => "bib0165"
              "etiqueta" => "33&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Resveratrol inhibits the expression of SREBP1 in cell model of steatosis via Sirt1-FOXO1 signaling pathway"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "Wang G&#46;L&#46;"
                            1 => "Fu Y&#46;C&#46;"
                            2 => "Xu W&#46;C&#46;"
                            3 => "Feng Y&#46;Q&#46;"
                            4 => "Fang S&#46;R&#46;"
                            5 => "Zhou X&#46;H&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.bbrc.2009.01.163"
                      "Revista" => array:6 [
                        "tituloSerie" => "Biochem Biophys Res Commun"
                        "fecha" => "2009"
                        "volumen" => "380"
                        "paginaInicial" => "644"
                        "paginaFinal" => "649"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19285015"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            33 => array:3 [
              "identificador" => "bib0170"
              "etiqueta" => "34&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Resveratrol improves non-alcoholic fatty liver disease by activating AMP-activated protein kinase"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "Shang J&#46;"
                            1 => "Chen L&#46;L&#46;"
                            2 => "Xiao F&#46;X&#46;"
                            3 => "Sun H&#46;"
                            4 => "Ding H&#46;C&#46;"
                            5 => "Xiao H&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1745-7254.2008.00807.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Acta Pharmacol Sin"
                        "fecha" => "2008"
                        "volumen" => "29"
                        "paginaInicial" => "698"
                        "paginaFinal" => "706"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18501116"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            34 => array:3 [
              "identificador" => "bib0175"
              "etiqueta" => "35&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Quercetin ameliorate insulin resistance and up-regulates cellular antioxidants during oleic acid induced hepatic steatosis in HepG2 cells"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "Vidyashankar S&#46;"
                            1 => "Sandeep Varma R&#46;"
                            2 => "Patki P&#46;S&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.tiv.2013.01.014"
                      "Revista" => array:6 [
                        "tituloSerie" => "Toxicol In Vitro"
                        "fecha" => "2013"
                        "volumen" => "27"
                        "paginaInicial" => "945"
                        "paginaFinal" => "953"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23348005"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            35 => array:3 [
              "identificador" => "bib0180"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The Potential of Flavonoids in the Treatment of Non-alcoholic Fatty Liver Disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "Van De Wier B&#46;"
                            1 => "Koek G&#46;H&#46;"
                            2 => "Bast A&#46;"
                            3 => "Haenen G&#46;R&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1080/10408398.2014.952399"
                      "Revista" => array:6 [
                        "tituloSerie" => "Crit Rev Food Sci Nutr"
                        "fecha" => "2017"
                        "volumen" => "57"
                        "paginaInicial" => "834"
                        "paginaFinal" => "855"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25897647"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            36 => array:3 [
              "identificador" => "bib0185"
              "etiqueta" => "37&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effects of resveratrol and other polyphenols in hepatic steatosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "Aguirre L&#46;"
                            1 => "Portillo M&#46;P&#46;"
                            2 => "Hijona E&#46;"
                            3 => "Bujanda L&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3748/wjg.v20.i23.7366"
                      "Revista" => array:6 [
                        "tituloSerie" => "World J Gastroenterol"
                        "fecha" => "2014"
                        "volumen" => "20"
                        "paginaInicial" => "7366"
                        "paginaFinal" => "7380"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24966607"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            37 => array:3 [
              "identificador" => "bib0190"
              "etiqueta" => "38&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Fatty Acid-Regulated Transcription Factors in the Liver"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "Jump D&#46;B&#46;"
                            1 => "Tripathy S&#46;"
                            2 => "Depner C&#46;M&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1146/annurev-nutr-071812-161139"
                      "Revista" => array:6 [
                        "tituloSerie" => "Annu Rev Nutr"
                        "fecha" => "2013"
                        "volumen" => "33"
                        "paginaInicial" => "249"
                        "paginaFinal" => "269"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23528177"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            38 => array:3 [
              "identificador" => "bib0195"
              "etiqueta" => "39&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
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                            5 => "Mimani M&#46;"
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                        "paginaInicial" => "613"
                        "paginaFinal" => "620"
                        "link" => array:1 [
                          0 => array:2 [
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                        "link" => array:1 [
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                        "paginaFinal" => "238"
                        "link" => array:1 [
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                          "autores" => array:2 [
                            0 => "Anderson N&#46;"
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                        "link" => array:1 [
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Article information

ISSN: 16652681
Original language: English

DOI:10.5604/01.3001.0010.8642

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	5	0	5
2024 October	18	3	21
2024 September	14	5	19
2024 August	19	5	24
2024 July	13	0	13
2024 June	10	2	12
2024 May	40	4	44
2024 April	27	4	31
2024 March	42	5	47
2024 February	35	1	36
2024 January	13	7	20
2023 December	20	2	22
2023 November	19	4	23
2023 October	11	4	15
2023 September	5	4	9
2023 August	14	9	23
2023 July	7	6	13
2023 June	25	4	29
2023 May	42	7	49
2023 April	46	2	48
2023 March	41	7	48
2023 February	33	7	40
2023 January	23	17	40
2022 December	24	7	31
2022 November	25	13	38
2022 October	22	9	31
2022 September	58	10	68
2022 August	27	6	33
2022 July	25	14	39
2022 June	21	15	36
2022 May	25	11	36
2022 April	22	10	32
2022 March	28	16	44
2022 February	9	9	18
2022 January	24	11	35
2021 December	10	9	19
2021 November	15	10	25
2021 October	37	11	48
2021 September	20	9	29
2021 August	23	6	29
2021 July	20	10	30
2021 June	23	8	31
2021 May	32	12	44
2021 April	89	8	97
2021 March	38	34	72
2021 February	28	9	37
2021 January	40	26	66
2020 December	28	13	41
2020 November	13	14	27
2020 October	15	7	22
2020 September	14	11	25
2020 August	18	7	25
2020 July	24	12	36
2020 June	30	3	33
2020 May	21	13	34
2020 April	25	3	28
2020 March	21	3	24
2020 February	20	7	27
2020 January	27	5	32
2019 December	20	7	27
2019 November	22	12	34
2019 October	15	10	25
2019 September	17	7	24
2019 August	11	3	14
2019 July	14	16	30
2019 June	16	23	39
2019 May	8	14	22

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