The preventive effect of liraglutide on the lipotoxic liver injury via increasing autophagy

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"documento" => "article" "crossmark" => 1 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "Ann Hepatol. 2020;19:53-61" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 232 "formatos" => array:3 [ "EPUB" => 8 "HTML" => 169 "PDF" => 55 ] ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "Original article" "titulo" => "Spleen Stiffness Probability Index (SSPI): A simple and accurate method to detect esophageal varices in patients with compensated liver cirrhosis" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "53" "paginaFinal" => "61" ] ] "contieneResumen" => array:1 [ "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0020" "etiqueta" => "Fig. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 840 "Ancho" => 3167 "Tamanyo" => 128040 ] ] "descripcion" => array:1 [ "en" => "Spleen Stiffness (left) and Liver Stiffness (right) distribution in Healthy Subjects, Cirrhotics without EVs and Cirrhotics with EVs. Values are reported in kPa (y-axis). Spleen Stiffness values have been found to overlap between healthy subjects and cirrhotic patients who have not developed EVs yet. 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"documento" => "article" "crossmark" => 1 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "Ann Hepatol. 2020;19:36-43" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 94 "formatos" => array:3 [ "EPUB" => 7 "HTML" => 54 "PDF" => 33 ] ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "Original article" "titulo" => "Hyperdynamic circulatory syndrome in a mouse model transgenic for SerpinB3" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "36" "paginaFinal" => "43" ] ] "contieneResumen" => array:1 [ "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0025" "etiqueta" => "Fig. 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr5.jpeg" "Alto" => 3737 "Ancho" => 1442 "Tamanyo" => 194916 ] ] "descripcion" => array:1 [ "en" => "Panel A: effect of SB3 (10−7M) on small resistance mesenteric arteries (isolated from to 5 WT Wistar-Kyoto rats) preconstricted with phenylephrine (10−6M). No significant variation in arterial diameter was observed. Panel B: concentration–response curve to phenylephrine (PHE) obtained in small resistance mesenteric arteries. The administration of SB3 increased the sensitivity to PHE of the arteries (two-way ANOVA: p<0.01). Panel C: concentration–response curve to PHE obtained in small resistance mesenteric arteries incubated with irbesartan (10−5M) to inhibit Angiotensin II type 1-receptors. After pre-incubation with irbesartan, the administration of SB3 did not modify the sensitivity to PHE of the arteries (two-way ANOVA: p: NS). Estimated of variance are±SD." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Gianmarco Villano, Alberto Verardo, Andrea Martini, Silvia Brocco, Paola Pesce, Erica Novo, Maurizio Parola, David Sacerdoti, Marco Di Pascoli, Marny Fedrigo, Chiara Castellani, Annalisa Angelini, Patrizia Pontisso, Massimo Bolognesi" "autores" => array:14 [ 0 => array:2 [ "nombre" => "Gianmarco" "apellidos" => "Villano" ] 1 => array:2 [ "nombre" => "Alberto" "apellidos" => "Verardo" ] 2 => array:2 [ "nombre" => "Andrea" "apellidos" => "Martini" ] 3 => array:2 [ "nombre" => "Silvia" "apellidos" => "Brocco" ] 4 => array:2 [ "nombre" => "Paola" "apellidos" => "Pesce" ] 5 => array:2 [ "nombre" => "Erica" "apellidos" => "Novo" ] 6 => array:2 [ "nombre" => "Maurizio" "apellidos" => "Parola" ] 7 => array:2 [ "nombre" => "David" "apellidos" => "Sacerdoti" ] 8 => array:2 [ "nombre" => "Marco" "apellidos" => "Di Pascoli" ] 9 => array:2 [ "nombre" => "Marny" "apellidos" => "Fedrigo" ] 10 => array:2 [ "nombre" => "Chiara" "apellidos" => "Castellani" ] 11 => array:2 [ "nombre" => "Annalisa" "apellidos" => "Angelini" ] 12 => array:2 [ "nombre" => "Patrizia" "apellidos" => "Pontisso" ] 13 => array:2 [ "nombre" => "Massimo" "apellidos" => "Bolognesi" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1665268119322331?idApp=UINPBA00004N" "url" => "/16652681/0000001900000001/v2_202001221934/S1665268119322331/v2_202001221934/en/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "Original article" "titulo" => "The preventive effect of liraglutide on the lipotoxic liver injury via increasing autophagy" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "44" "paginaFinal" => "52" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Yini He, Na Ao, Jing Yang, Xiaochen Wang, Shi Jin, Jian Du" "autores" => array:6 [ 0 => array:3 [ "nombre" => "Yini" "apellidos" => "He" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 1 => array:3 [ "nombre" => "Na" "apellidos" => "Ao" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "Jing" "apellidos" => "Yang" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 3 => array:3 [ "nombre" => "Xiaochen" "apellidos" => "Wang" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 4 => array:3 [ "nombre" => "Shi" "apellidos" => "Jin" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 5 => array:4 [ "nombre" => "Jian" "apellidos" => "Du" "email" => array:2 [ 0 => "cmu1hyn@163.com" 1 => "duj2019@126.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Department of General Practice, The First Hospital of China Medical University, Shenyang, Liaoning, China" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Department of Endocrinology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Department of Endocrinology, The People's Hospital of Liaoning Province, Shenyang, Liaoning, China" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author at: Department of Endocrinology. The Fourth Appiliated Hospital of China Medical University, Shenyang, Liaoning, China" ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1261 "Ancho" => 2917 "Tamanyo" => 558209 ] ] "descripcion" => array:1 [ "en" => "Histopathological changes in rat livers 16 weeks after HFD. A. Histopathological changes (× 200); B. Rat liver histopathological NAS scores; C. 50L group: low dose liraglutide intervention group (50μg/kg), D. 100L group: middle dose liraglutide intervention group (100μg/kg), E. 200L group: high-dose liraglutide intervention group (200μg/kg)." ] ] ] "textoCompleto" => "1IntroductionAt present, non-alcoholic fatty liver disease (NAFLD) is prevalent and keeps rising. In developed countries, about 80% of adults with obesity or diabetes has been suffering from NAFLD <a class="elsevierStyleCrossRefs" href="#bib0200">[1,2]</a>, and the NAFLDs has relatively higher risk of liver fibrosis and liver cancer <a class="elsevierStyleCrossRefs" href="#bib0210">[3,4]</a>. It is generally believed that NAFLD is closely related to insulin resistance, obesity, diabetes, dyslipidemia, and other metabolic syndromes that clinically manifest in the liver <a class="elsevierStyleCrossRefs" href="#bib0220">[5–7]</a>. NAFLD includes simple fatty liver, fatty hepatitis, and fatty liver-related cirrhosis, which can develop into liver cancer <a class="elsevierStyleCrossRef" href="#bib0235">[8]</a>. NAFLD has also been considered as a high risk to induce cardiovascular and cerebrovascular diseases <a class="elsevierStyleCrossRef" href="#bib0240">[9]</a>.It is well understood that insulin resistance leads to excessive intake of free fatty acids (FFA) caused by steatosis. In addition, other factors, including oxidative stress injury, lipid peroxidation and abnormal cytokines, can cause local inflammatory changes that cause steatohepatitis in the hepatic lobules <a class="elsevierStyleCrossRef" href="#bib0245">[10]</a>. While this ‘two-hit’ hypothesis is currently widely accepted, NAFLD pathogenesis is not yet fully understood <a class="elsevierStyleCrossRef" href="#bib0250">[11]</a>. Excessive lipid deposition in the liver has been considered the primary factor that induces liver lipotoxicity <a class="elsevierStyleCrossRefs" href="#bib0255">[12–14]</a>. Additionally, autophagy has been closely associated with intrahepatic lipid deposition. Previous studies have shown that autophagy degrades fat in hepatocytes as a relatively fixed process of auto-catabolism <a class="elsevierStyleCrossRefs" href="#bib0270">[15–17]</a>. Autophagy can also promote “self-digestion” of accumulated, failing protein aggregates and defective organelles within the cell to maintain stability in the intracellular environment <a class="elsevierStyleCrossRefs" href="#bib0285">[18,19]</a>. Lipid drops (LDs), which are biodegradation substrates, can be annexed and decomposed by the lysosomal pathway to maintain balanced intracellular lipid metabolism. Decreased intrahepatic autophagic activity, both in vitro and in vivo, can induce excessive lipid deposition <a class="elsevierStyleCrossRef" href="#bib0295">[20]</a>.Evidence indicates that glucagon like peptide-1 (GLP-1) protects the liver from cell apoptosis induced by fatty acids though promoting autophagy and suppressing dysfunctional endoplasmic reticulum stress <a class="elsevierStyleCrossRefs" href="#bib0300">[21,22]</a>. AMP-activated protein kinase (AMPK) is a cellular energy sensor that plays a key role in metabolic disorders and cancer <a class="elsevierStyleCrossRef" href="#bib0310">[23]</a>. The AMPK pathway is thought to critically regulate autophagy <a class="elsevierStyleCrossRef" href="#bib0315">[24]</a>. More specifically, AMPK activation can inhibit metabolic pathways and activate catabolic pathways to promote effective energy expenditure, which consequently improves how cells adapt to metabolic stress, resulting in increased cell survival <a class="elsevierStyleCrossRefs" href="#bib0310">[23,25]</a>.Previous studies showed that GLP-1 improves hepatocyte steatosis by inducing autophagy through activating AMPK <a class="elsevierStyleCrossRef" href="#bib0325">[26]</a> in mice, suggesting that AMPK protects pancreatic β-cells from high glucose <a class="elsevierStyleCrossRef" href="#bib0330">[27]</a>. This evidence provides a new direction for targeting GLP-1 to prevent further deterioration of hepatic steatosis in NAFLD patients. However, the effect of GLP-1 analogs on high-fat diet (HFD)-induced NAFLD in rats has not been investigated. Further, the mechanism underlying liraglutide-induced autophagy is currently unknown. In the current study, we confirmed that liraglutide enhances autophagy in liver tissue and improves hepatic steatosis in a HFD-induced rat model of NAFLD. In addition, we provide evidence supporting the potential mechanism involving activation of the AMPK-mTOR pathway in liver homeostasis.2Materials and methods2.1AnimalsMale Sprague–Dawley rats (n=50, 5 weeks of age, approximately 100g) obtained from the Laboratory Animal Center of China Medical University were used to establish the NAFLD model. All rats were acclimated for one week prior to experimentation according to a previous protocol published <a class="elsevierStyleCrossRef" href="#bib0335">[28]</a>. Briefly, two initial groups of rats were randomly separated. The normal control (NC) group (n=13) was fed chow containing 62% carbohydrates, 10% fat, and 28% protein; the HFD group (n=37) was fed chow containing 34% carbohydrates, 52% fat, and 14% protein. Five rats from each group were randomly selected to confirm successful establishment of NAFLD after 12 weeks of feeding. (All animals received humane care according to the criteria outlined in the “Guide for the Care and Use of Laboratory Animals” prepared by the National Academy of Sciences and published by the National Institutes of Health.)Rats in the HFD group were randomly subdivided into four groups: HFD, 50L, 100L, and 200L (n=8 in each group). Rats in the HFD group were continually fed a HFD and were given 0.5ml/kg of normal saline as needed. Rats in the 50L, 100L, and 200L groups continued to receive HFD with different doses of liraglutide (L) (50, 100, or 200μg/kg) (Victoza, Novo-Nordisk A/S, Denmark), respectively. The rats in the NC group (n=8) continued to receive normal chow and were injected with 0.5ml/kg of normal saline. Saline and liraglutide were injected subcutaneously at 8:00am and 8:00pm every day for 4 weeks.2.2Cell culture and treatmentHepG2 cells were cultured at 37°C in a humidified chamber with 5% CO2 and maintained in Dulbecco's modified Eagle's medium (DMEM, Gibco) containing 10% heat-inactivated fetal bovine serum (FBS, Gibco). There were a total of six cell culture groups: Control group treated with serum-free bovine serum albumin (BSA; Sigma–Aldrich, USA) medium; PA group treated with or without 400M palmitate fatty acid (PA) for 24h; and experimental groups treated with 400M PA and either 10, 50, l00, or 500nmol/L liraglutide for 24h, respectively. These cells were divided into four groups: normal HepG2 cells (BSA), treated with PA (PA), treated with PA and liraglutide (100G), and Compound C for 30min and then treated with PA and liraglutide (100G+C). Command C is an AMPK pathway inhibitor.2.3Western blot analysisLiver specimens and whole-cell extracts were homogenized and centrifuged in RIPA buffer (Beyotime Institute of Biotechnology, China) containing a protease inhibitor cocktail with 1mmol/L phenylmethanesulfonyl fluoride (Beyotime) on ice. Protein lysates were quantified using the BCA assay as previous described <a class="elsevierStyleCrossRef" href="#bib0335">[28]</a> (Pierce, USA). 50μg of protein for each sample were separated by 8–10% SDS-PAGE and transferred to PVDF membranes (Millipore, USA). The membranes were blocked with 5% BSA and then incubated with primary antibodies against microtubule-associated protein LC3, Beclin1, AMPK, phosphorylated (p)-AMPK, TSC1, mTOR, and p-mTOR (all of which were used at 1:1000 and purchased from Cell Signaling Technology, USA) and GAPDH (used at 1:1000; Santa Cruz, CA, USA) at 4°C overnight. The horseradish peroxidase-conjugated anti-rabbit, anti-goat, or anti-mouse secondary antibodies (1:5000, all from Santa Cruz Biotechnology, Inc.) were added at room temperature for 2h after 3 washes (10min each). The immunological complexes were visualized with Micro Chemi 4.2 (DNR Bio-Imaging Systems Ltd., Jerusalem, Israel). Quantity One Software (Bio-Rad, USA) was used to quantify the protein band intensity.2.4Real-time RT-PCRTotal RNA from the frozen liver specimens (100mg) and cell cultures were isolated using Trizol reagent (Takara Biotechnology Co., Ltd.). The PrimeScriptTM RT reagent kit was used to synthesize cDNA (Takara Biotechnology Co., Ltd., Dalian, China).Real-time RT-PCR analysis was performed with a Thermal Cycler Dice Real Time detection System (Takara Bio Inc., Japan) using the SYBR Premix Ex Taq II kit (Tli RNaseH Plus) (Takara Biotechnology Co., Ltd.). Gene-specific primers for GFAP and GAPDH were purchased from Takara Biotechnology Co., Ltd. The following PCR protocol was used for all genes: reverse transcription step for 15min at 37°C, then denaturation at 85°C for 5s, 4°C for 7min, followed by an additional 40 cycles of amplification and quantification (5s at 95°C; 30s at 60°C; 30s at 60°C). mRNA expression was normalized to GAPDH as a housekeeping gene. The primers were designed (Primer Premier 5.0) and synthesized (Takara Biotechnology Co., Ltd. Dalian, China). For each gene, the relative change of mRNA in the samples was calculated by subtracting GAPDH Ct values from Ct values for the gene of interest using the 2−ΔΔCt method.2.5Electron microscopyFor transmission electron microscopy (TEM), liver specimens were fixed with 2.5% glutaraldehyde in a 0.1M sodium cacodylate, pH 7.4, buffer at 4°C and then minced into small (1mm3) fragments. After washing with 0.1M phosphate buffered saline (PBS) three times for 15min each, the liver tissue samples were fixed in 1% osmium tetroxide (OSO4) for 1h, followed by washes in 0.1M PBS. Liver tissues were gradually dehydrated in ethanol solutions of 20%, 50%, 70% and 90% and embedded in Epon 812 epoxy resin before ultrathin sectioning. The ultrastructure of the sections was visualized using a JEM-1200EX electron microscope (JEOL Co., Japan) in the TEM laboratory of China Medical University.2.6Hematoxylin and eosin (HE) StainingThe liver tissues were fixed at 5mm from the edge of the right lobe of the liver and immersed in 4% paraformaldehyde. Then the tissues were dehydrated, waxed, embedded, and sliced for HE staining. Samples were dewaxed, benzenes were removed, hydrated, hematoxylin stained, washed, eosin stained, dehydrated, and imaged. According to the 2010 guidelines for the diagnosis and treatment of NLFD liver histopathological sections were scored based on the NAS system (0 to 8 points): (1) hepatocellular steatosis: 0 points (<5%); 1 point (5–33%); 2 points (34–66%); 3 points (>66%); (2) Inflammation within the lobules (inflammatory necrosis at 20-fold microscopy): 0 points (none), 1 point (<2), 2 points (2–4), 3 points (>4); (3) liver cell ballooning: 0 points, no; 1 point, rare; 2 points, more common.2.7Statistical analysisAll data are expressed as the mean±standard deviation (SD) and calculated with one-way analysis of variance (ANOVA) followed by a Newman–Keuls post-hoc test (SPSS 17.0). Results of comparisons were considered significantly different if the p value was<0.05.3Results3.1Liraglutide improves hepatic histology during NAFLD developmentAfter 16 weeks of HFD or normal chow diet we examined the histological features of the livers from NAFLD and NC mice. The liver surfaces were greyish yellow and the edges were blunt and thick in the HFD group compared to the NC group, in which the livers were bright red with sharp edges. Liraglutide dose-dependently ameliorated the pathological hepatic histology in the HFD group (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>A–E).<elsevierMultimedia ident="fig0005"></elsevierMultimedia>As shown in <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>A–E, liraglutide improved the hepatic histology by significantly reducing both fatty droplets and inflammatory foci number. NAS quantification of liver sections further confirmed the beneficial effects of liraglutide treatment on hepatic histology (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). Compared to the NC rats, the HFD rats had more hepatocellular steatosis (P<0.05), but liraglutide dose-dependently and significantly decreased steatosis, inflammation, and ballooning in the HFD group compared to the NC group (P<0.05).<elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0005"></elsevierMultimedia>3.2Liraglutide improves autophagy in the NAFLD rat modelWe used electron microscopy to measure autophagosomes in each group. We found that the number of autophagosomes in the HFD group was significantly lower compared to the NC group. Liraglutide treatment dose-dependently increased the number of autophagocytic bodies in the HFD group compared to the NC group (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>A and B).<elsevierMultimedia ident="fig0015"></elsevierMultimedia>To further determine whether liraglutide improves autophagy in HFD-induced NAFLD rats, we measured the expression of autophagy-related proteins, LC3, Beclin1 and Atg7, in liver tissues. We found that LC3, Beclin1 and Atg7 mRNA levels and protein expression were significantly reduced in the HFD group and that liraglutide treatment dramatically increased expression of these autophagy markers (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>A–F).<elsevierMultimedia ident="fig0020"></elsevierMultimedia>3.3Liraglutide improves autophagy in HepG2 cell in vitroWe measured mRNA and protein expression of the autophagy-related proteins, LC3, Beclin1 and Atg7, in HepG2 cells following PA treatment. In the PA group, mRNA and protein expression of LC3, Beclin1 and Atg7 were significantly lower compared to the BSA group (P<0.01). However, liraglutide dose-dependently increased the mRNA and protein levels of LC3, Beclin1 and Atg7 relative to the PA group (P<0.01) (<a class="elsevierStyleCrossRef" href="#fig0025">Fig. 5</a>A–F).<elsevierMultimedia ident="fig0025"></elsevierMultimedia>3.4The effect of liraglutide on autophagy in HepG2 cells following AMPK pathway inhibitionTo investigate whether the AMPK pathway was involved in liraglutide-mediated improvement of autophagy after PA treatment, we measured protein levels of LC3, Beclin1 and Atg7 in HepG2 cells. The results showed that the levels of LC3, Beclin1 and Atg7 were significantly higher in the liraglutide intervention group (100G group) compared to the PA group (P<0.01). However, LC3, Beclin1 and Atg7 levels were significantly lower in the inhibition group (100G+C) containing Compound C, PA (400mmol/L) and liraglutide (100nmol/L), compared to the 100G group (P<0.01) (<a class="elsevierStyleCrossRef" href="#fig0030">Fig. 6</a>A–C).<elsevierMultimedia ident="fig0030"></elsevierMultimedia>3.5Effects of liraglutide on AMPK pathway-associated proteins following AMPK pathway inhibitionWe measured expression of AMPK pathway-associated proteins to confirm that liraglutide-mediated autophagy induced by PA could be reversed by inhibiting the AMPK pathway. As shown in <a class="elsevierStyleCrossRef" href="#fig0030">Fig. 6</a>, the levels of p-AMPK/AMPK, TSC1, p-mTOR/mTOR were decreased (P<0.01) in the PA group (400μmol/L PA) compared to the control group (BSA group). Furthermore, the levels of p-AMPK/AMPK, TSC1, and p-mTOR/mTOR were increased in the liraglutide intervention group (100G group) compared to the PA group (P<0.05). The levels of p-AMPK/AMPK, TSC1, p-mTOR/mTOR were significantly lower than those in the 100G group compared to the inhibition group (100 G+C) containing Compound C, PA (400μmol/L), and liraglutide (100nmol/L) (P<0.01) (<a class="elsevierStyleCrossRef" href="#fig0035">Fig. 7</a>A–C).<elsevierMultimedia ident="fig0035"></elsevierMultimedia>4DiscussionThe prevalence of NAFLD has increased worldwide, affecting both adults and children. Liraglutide, a GLP-1 analog, has been reported to decrease lipid deposition and inflammation in hepatocytes <a class="elsevierStyleCrossRefs" href="#bib0340">[29,30]</a>. However, few studies have investigated whether liraglutide can improve hepatic lipid accumulation in NAFLD. In the current study, we used an established rat model of HFD-induced NAFLD and demonstrated that liraglutide significantly decreased the number of autophagosomes. Liraglutide treatment dose-dependently improved autophagy, which was confirmed by measuring expression of autophagy-related proteins invivo and in vitro. More importantly, the AMPK pathway inhibitor, Compound C, reversed liraglutide's effects on autophagy following PA treatment in vitro, which suggests that liraglutide-induced autophagy is mediated by the AMPK signaling pathway.Autophagy is an intracellular pathway that maintains normal cellular function by promoting turnover of long-lived proteins <a class="elsevierStyleCrossRef" href="#bib0350">[31]</a>. Studies have demonstrated that enhanced autophagy can rescue pancreatic β-cells from glucotoxicity, and inhibition of autophagy augments caspase-3 activation <a class="elsevierStyleCrossRef" href="#bib0355">[32]</a>, suggesting that autophagy might protect against Type 2 Diabetes. Previous evidence indicated that autophagy is suppressed in the presence of hyper-insulinemia induced by HFD in mice <a class="elsevierStyleCrossRef" href="#bib0360">[33]</a>, which was consistent with our results; however, we note that we used a different animal model in our study. Our results indicate that autophagy was significantly decreased in the NAFLD rat model, since the autophagy-related proteins, LC3, Beclin1 and Atg7, were significantly reduced at both the mRNA and protein levels. We also noticed that autophagy-related protein levels were decreased in palmitate-induced lipotoxicity in HepG2 cells in vitro, which mimics the pathogenic features of the NAFLD model in vivo.Liraglutide, a GLP-1 analog, regulates β-cell mass via multiple pathways <a class="elsevierStyleCrossRefs" href="#bib0365">[34–36]</a>. Liraglutide was proven to decrease lipid accumulation in the steatotic LO2 cell model <a class="elsevierStyleCrossRef" href="#bib0380">[37]</a> and protect pancreatic β-cells from high glucose by enhancing autophagy via AMPK <a class="elsevierStyleCrossRef" href="#bib0325">[26]</a>. It is also known that GLP-1 exerts protective effects on hepatic steatosis <a class="elsevierStyleCrossRef" href="#bib0385">[38]</a>. In the present study, we found that the general appearance, histopathological changes, and the number of autophagic bodies in the livers of NAFLD rats improved after liraglutide treatment. Further evidence showed that liraglutide does-dependently increased the expression of autophagy-related proteins in rats fed a HFD and in HepG2 cells treated with PA. These results suggest that GLP-1 ameliorates HFD induced NAFLD by activating autophagy.Existing research shows that the AMPK/mTOR pathway regulates downstream signaling to trigger autophagy <a class="elsevierStyleCrossRef" href="#bib0390">[39]</a>. AMPK could negatively affect liraglutide-induced increases in cell viability and autophagy to protect insulin-1 pancreatic β-cells from glucotoxicity in rats <a class="elsevierStyleCrossRef" href="#bib0330">[27]</a>. In addition, AMPK/mTOR signaling was involved in hepatic lipid metabolism induced by GLP-1 <a class="elsevierStyleCrossRef" href="#bib0325">[26]</a>.Our data revealed that Command C, an AMPK pathway inhibitor, reversed the enhanced autophagy induced by liraglutide in HepG2 cells treated with PA, which suggests that liraglutide intervention activates AMPK and up-regulates autophagy. Thus, we conclude that the AMPK pathway plays an important role in regulating autophagy induced by liraglutide.In conclusion, the current study demonstrates that liraglutide can improve hepatic steatosis via activating the AMPK pathway. These data suggest that GLP-1 may play a protective role in several models of NAFLD and that modulation of AMPK could be a potential target for lipid metabolic disorders.AbbreviationsAMPKadenosine 5′-monophosphate (AMP)-activated protein kinaseAtg7autophagy related gene 7Beclin1heterozygous disruption of beclin1cAMPcyclic adenosine monophosphateGLP-1glucagon-like peptide-1LC3micro-tubule-associated protein1 light chain 3mTORthe mammalian target of rapamycinNAFLDnonalcoholic fatty liver diseasePApalmitateT2DMtype 2 diabetes mellitusTSC1tuberous sclerosis-1Author's contributionDescription of author roles in manuscript creation: Jian Du designed the experiment. Yini He, Na Ao and Jing Yang performed the performed experiments, Xiaochen Wang and Shi Jin processed the data, Yini He wrote the paper, and Jian Du modified the paper.FundingThe Science and Technology Agency of Liao Ning (20170520272); The Hall Education of Liaoning (L2015567) (LQNK201715).Conflict of interestAll authors declare no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres1289625" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction and objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Materials and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1191509" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 3 => array:3 [ "identificador" => "sec0010" "titulo" => "Materials and methods" "secciones" => array:7 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Animals" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Cell culture and treatment" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Western blot analysis" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Real-time RT-PCR" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Electron microscopy" ] 5 => array:2 [ "identificador" => "sec0040" "titulo" => "Hematoxylin and eosin (HE) Staining" ] 6 => array:2 [ "identificador" => "sec0045" "titulo" => "Statistical analysis" ] ] ] 4 => array:3 [ "identificador" => "sec0050" "titulo" => "Results" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0055" "titulo" => "Liraglutide improves hepatic histology during NAFLD development" ] 1 => array:2 [ "identificador" => "sec0060" "titulo" => "Liraglutide improves autophagy in the NAFLD rat model" ] 2 => array:2 [ "identificador" => "sec0065" "titulo" => "Liraglutide improves autophagy in HepG2 cell in vitro" ] 3 => array:2 [ "identificador" => "sec0070" "titulo" => "The effect of liraglutide on autophagy in HepG2 cells following AMPK pathway inhibition" ] 4 => array:2 [ "identificador" => "sec0075" "titulo" => "Effects of liraglutide on AMPK pathway-associated proteins following AMPK pathway inhibition" ] ] ] 5 => array:2 [ "identificador" => "sec0080" "titulo" => "Discussion" ] 6 => array:2 [ "identificador" => "sec0085" "titulo" => "Author's contribution" ] 7 => array:2 [ "identificador" => "sec0090" "titulo" => "Funding" ] 8 => array:2 [ "identificador" => "sec0095" "titulo" => "Conflict of interest" ] 9 => array:2 [ "identificador" => "xack443389" "titulo" => "Acknowledgments" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2019-02-25" "fechaAceptado" => "2019-06-25" "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1191509" "palabras" => array:5 [ 0 => "GLP-1" 1 => "AMPK" 2 => "NAFLD" 3 => "Hepatic steatosis" 4 => "Treatment" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "Introduction and objectivesThe incidence of non-alcoholic fatty liver disease (NAFLD) is increasing. Previous studies indicated that Liraglutide, glucagon-like peptide-1 analogue, could regulate glucose homeostasis as a valuable treatment for Type 2 Diabetes. However, the precise effect of Liraglutide on NAFLD model in rats and the mechanism remains unknown. In this study, we investigated the molecular mechanism by which Liraglutide ameliorates hepatic steatosis in a high-fat diet (HFD)-induced rat model of NAFLD in vivo and in vitro. Materials and methodsNALFD rat models and hepatocyte steatosis in HepG2 cells were induced by HFD and palmitate fatty acid treatment, respectively. AMPK inhibitor, Compound C was added in HepG2 cells. Autophagy-related proteins LC3, Beclin1 and Atg7, and AMPK pathway-associated proteins were evaluated by Western blot and RT-PCR. ResultsLiraglutide enhanced autophagy as showed by the increased expression of the autophagy markers LC3, Beclin1 and Atg7 in HFD rats and HepG2 cells treated with palmitate fatty acid. In vitro, The AMPK inhibitor exhibited an inhibitory effect on Liraglutide-induced autophagy enhancement with the deceased expression of LC3, Beclin1 and Atg7. Additionally, Liraglutide treatment elevated AMPK levels and TSC1, decreased p-mTOR expression. ConclusionsLiraglutide could upregulate autophagy to decrease lipid over-accumulation via the AMPK/mTOR pathway." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction and objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Materials and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] ] "multimedia" => array:8 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1420 "Ancho" => 2833 "Tamanyo" => 303501 ] ] "descripcion" => array:1 [ "en" => "The general changes in liver tissue after 16 weeks of HFD. A. NC group, B. HFD control group, C. 50L group: low dose liraglutide intervention group (50μg/kg), D. 100L group: middle dose liraglutide intervention group (100μg/kg), E. 200L group: high-dose liraglutide intervention group (200μg/kg)." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1261 "Ancho" => 2917 "Tamanyo" => 558209 ] ] "descripcion" => array:1 [ "en" => "Histopathological changes in rat livers 16 weeks after HFD. A. Histopathological changes (× 200); B. Rat liver histopathological NAS scores; C. 50L group: low dose liraglutide intervention group (50μg/kg), D. 100L group: middle dose liraglutide intervention group (100μg/kg), E. 200L group: high-dose liraglutide intervention group (200μg/kg)." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 2593 "Ancho" => 2833 "Tamanyo" => 517708 ] ] "descripcion" => array:1 [ "en" => "Ultrastructure of hepatocytes observed by electron microscopy. A. NC group, B. HF group, C. 50L group: low dose liraglutide intervention group (50μg/kg), D. 100L group: middle dose liraglutide intervention group (100μg/kg), E. 200L group: high-dose liraglutide intervention group (200μg/kg). N, nucleus; LD, lipid droplet; →, autophagy body." ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Fig. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 3921 "Ancho" => 2509 "Tamanyo" => 390688 ] ] "descripcion" => array:1 [ "en" => "Liraglutide reversed the decrease in autophagy related proteins in HFD-induce NAFLD rats. A and B. LC3II mRNA expression and LC3II/LC3I protein were assessed by real-time RT-PCR and Western blot, respectively. C and D. Beclin1 mRNA and protein expression were detected by real-time RT-PCR and Western blot, respectively. E and F. Atg7 mRNA and protein expression were measured by real-time RT-PCR and Western blot, respectively." ] ] 4 => array:7 [ "identificador" => "fig0025" "etiqueta" => "Fig. 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr5.jpeg" "Alto" => 4189 "Ancho" => 2904 "Tamanyo" => 458221 ] ] "descripcion" => array:1 [ "en" => "Liraglutide reversed the decrease in autophagy related proteins in HepG2 cells. A and B. LC3II mRNA and protein expression were assessed by real-time RT-PCR and Western blot, respectively. C and D. Beclin1 mRNA and protein expression were detected by real-time RT-PCR and Western blot, respectively. E and F. Atg7 mRNA and protein expression were measured by real-time RT-PCR and Western blot, respectively." ] ] 5 => array:7 [ "identificador" => "fig0030" "etiqueta" => "Fig. 6" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr6.jpeg" "Alto" => 4359 "Ancho" => 1158 "Tamanyo" => 226215 ] ] "descripcion" => array:1 [ "en" => "The effect of liraglutide on autophagy in HepG2 cells in the presence of the AMPK pathway inhibitor. A. Expression of LC3II/LC3I detected by Western blot with or without the AMPK pathway inhibitor. B. Expression of Beclin1 detected by Western blot with or without the AMPK pathway inhibitor. C. Expression of Atg7 detected by Western blot with or without the AMPK pathway inhibitor." ] ] 6 => array:7 [ "identificador" => "fig0035" "etiqueta" => "Fig. 7" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr7.jpeg" "Alto" => 3221 "Ancho" => 2718 "Tamanyo" => 242337 ] ] "descripcion" => array:1 [ "en" => "Effects of liraglutide on AMPK pathway-associated proteins in the presence of the AMPK pathway inhibitor. A. Expression of p-AMPK/AMPK detected by Western blot. B. Expression of TSC1 detected by Western blot. C. Expression of p-mTOR/mTOR detected by Western blot." ] ] 7 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_rowhead " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Group \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Steatosis \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Inflammatory necrosis \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Balloon-like changes \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.28 ±0.48 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.29 ±0.48 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.80±0.38<a class="elsevierStyleCrossRef" href="#tblfn0005">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.85±0.38<a class="elsevierStyleCrossRef" href="#tblfn0005">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.57±0.53<a class="elsevierStyleCrossRef" href="#tblfn0005">*</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">50L \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.29±0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.00±0.00<a class="elsevierStyleCrossRef" href="#tblfn0010">#</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.85±0.38<a class="elsevierStyleCrossRef" href="#tblfn0010">#</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">100L \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.13±0.53<a class="elsevierStyleCrossRef" href="#tblfn0010">#</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.71±0.56<a class="elsevierStyleCrossRef" href="#tblfn0010">#</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.42±0.54<a class="elsevierStyleCrossRef" href="#tblfn0010">#</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">200L \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.37±0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.25±0.52<a class="elsevierStyleCrossRef" href="#tblfn0010">#</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.13±0.35<a class="elsevierStyleCrossRef" href="#tblfn0010">#</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2208708.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "*" "nota" => "Compared to NC group,P<0.05" ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "#" "nota" => "compared to HF group,P<0.05" ] ] ] "descripcion" => array:1 [ "en" => "The NAS scores of hepatic pathological sections after 16 weeks of HFD" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:39 [ 0 => array:3 [ "identificador" => "bib0200" "etiqueta" => "[1]" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Epidemiology and risk factors of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH)" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "R. 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Yini Hea, Na Aob, Jing Yangb, Xiaochen Wangc, Shi Jinb, Jian Dub,

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cmu1hyn@163.com
duj2019@126.com

Corresponding author at: Department of Endocrinology. The Fourth Appiliated Hospital of China Medical University, Shenyang, Liaoning, China

a Department of General Practice, The First Hospital of China Medical University, Shenyang, Liaoning, China

b Department of Endocrinology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China

c Department of Endocrinology, The People's Hospital of Liaoning Province, Shenyang, Liaoning, China

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    "titulo" => "The preventive effect of liraglutide on the lipotoxic liver injury via increasing autophagy"
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          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Histopathological changes in rat livers 16 weeks after HFD&#46; A&#46; Histopathological changes &#40;&#215; 200&#41;&#59; B&#46; Rat liver histopathological NAS scores&#59; C&#46; 50<span class="elsevierStyleHsp" style=""></span>L group&#58; low dose liraglutide intervention group &#40;50<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;kg&#41;&#44; D&#46; 100<span class="elsevierStyleHsp" style=""></span>L group&#58; middle dose liraglutide intervention group &#40;100<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;kg&#41;&#44; E&#46; 200<span class="elsevierStyleHsp" style=""></span>L group&#58; high-dose liraglutide intervention group &#40;200<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;kg&#41;&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">1</span><span class="elsevierStyleSectionTitle" id="sect0035">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">At present&#44; non-alcoholic fatty liver disease &#40;NAFLD&#41; is prevalent and keeps rising&#46; In developed countries&#44; about 80&#37; of adults with obesity or diabetes has been suffering from NAFLD <a class="elsevierStyleCrossRefs" href="#bib0200">&#91;1&#44;2&#93;</a>&#44; and the NAFLDs has relatively higher risk of liver fibrosis and liver cancer <a class="elsevierStyleCrossRefs" href="#bib0210">&#91;3&#44;4&#93;</a>&#46; It is generally believed that NAFLD is closely related to insulin resistance&#44; obesity&#44; diabetes&#44; dyslipidemia&#44; and other metabolic syndromes that clinically manifest in the liver <a class="elsevierStyleCrossRefs" href="#bib0220">&#91;5&#8211;7&#93;</a>&#46; NAFLD includes simple fatty liver&#44; fatty hepatitis&#44; and fatty liver-related cirrhosis&#44; which can develop into liver cancer <a class="elsevierStyleCrossRef" href="#bib0235">&#91;8&#93;</a>&#46; NAFLD has also been considered as a high risk to induce cardiovascular and cerebrovascular diseases <a class="elsevierStyleCrossRef" href="#bib0240">&#91;9&#93;</a>&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">It is well understood that insulin resistance leads to excessive intake of free fatty acids &#40;FFA&#41; caused by steatosis&#46; In addition&#44; other factors&#44; including oxidative stress injury&#44; lipid peroxidation and abnormal cytokines&#44; can cause local inflammatory changes that cause steatohepatitis in the hepatic lobules <a class="elsevierStyleCrossRef" href="#bib0245">&#91;10&#93;</a>&#46; While this &#8216;two-hit&#8217; hypothesis is currently widely accepted&#44; NAFLD pathogenesis is not yet fully understood <a class="elsevierStyleCrossRef" href="#bib0250">&#91;11&#93;</a>&#46; Excessive lipid deposition in the liver has been considered the primary factor that induces liver lipotoxicity <a class="elsevierStyleCrossRefs" href="#bib0255">&#91;12&#8211;14&#93;</a>&#46; Additionally&#44; autophagy has been closely associated with intrahepatic lipid deposition&#46; Previous studies have shown that autophagy degrades fat in hepatocytes as a relatively fixed process of auto-catabolism <a class="elsevierStyleCrossRefs" href="#bib0270">&#91;15&#8211;17&#93;</a>&#46; Autophagy can also promote &#8220;self-digestion&#8221; of accumulated&#44; failing protein aggregates and defective organelles within the cell to maintain stability in the intracellular environment <a class="elsevierStyleCrossRefs" href="#bib0285">&#91;18&#44;19&#93;</a>&#46; Lipid drops &#40;LDs&#41;&#44; which are biodegradation substrates&#44; can be annexed and decomposed by the lysosomal pathway to maintain balanced intracellular lipid metabolism&#46; Decreased intrahepatic autophagic activity&#44; both <span class="elsevierStyleItalic">in vitro</span> and <span class="elsevierStyleItalic">in vivo</span>&#44; can induce excessive lipid deposition <a class="elsevierStyleCrossRef" href="#bib0295">&#91;20&#93;</a>&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Evidence indicates that glucagon like peptide-1 &#40;GLP-1&#41; protects the liver from cell apoptosis induced by fatty acids though promoting autophagy and suppressing dysfunctional endoplasmic reticulum stress <a class="elsevierStyleCrossRefs" href="#bib0300">&#91;21&#44;22&#93;</a>&#46; AMP-activated protein kinase &#40;AMPK&#41; is a cellular energy sensor that plays a key role in metabolic disorders and cancer <a class="elsevierStyleCrossRef" href="#bib0310">&#91;23&#93;</a>&#46; The AMPK pathway is thought to critically regulate autophagy <a class="elsevierStyleCrossRef" href="#bib0315">&#91;24&#93;</a>&#46; More specifically&#44; AMPK activation can inhibit metabolic pathways and activate catabolic pathways to promote effective energy expenditure&#44; which consequently improves how cells adapt to metabolic stress&#44; resulting in increased cell survival <a class="elsevierStyleCrossRefs" href="#bib0310">&#91;23&#44;25&#93;</a>&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Previous studies showed that GLP-1 improves hepatocyte steatosis by inducing autophagy through activating AMPK <a class="elsevierStyleCrossRef" href="#bib0325">&#91;26&#93;</a> in mice&#44; suggesting that AMPK protects pancreatic &#946;-cells from high glucose <a class="elsevierStyleCrossRef" href="#bib0330">&#91;27&#93;</a>&#46; This evidence provides a new direction for targeting GLP-1 to prevent further deterioration of hepatic steatosis in NAFLD patients&#46; However&#44; the effect of GLP-1 analogs on high-fat diet &#40;HFD&#41;-induced NAFLD in rats has not been investigated&#46; Further&#44; the mechanism underlying liraglutide-induced autophagy is currently unknown&#46; In the current study&#44; we confirmed that liraglutide enhances autophagy in liver tissue and improves hepatic steatosis in a HFD-induced rat model of NAFLD&#46; In addition&#44; we provide evidence supporting the potential mechanism involving activation of the AMPK-mTOR pathway in liver homeostasis&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2</span><span class="elsevierStyleSectionTitle" id="sect0040">Materials and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;1</span><span class="elsevierStyleSectionTitle" id="sect0045">Animals</span><p id="par0025" class="elsevierStylePara elsevierViewall">Male Sprague&#8211;Dawley rats &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>50&#44; 5 weeks of age&#44; approximately 100<span class="elsevierStyleHsp" style=""></span>g&#41; obtained from the Laboratory Animal Center of China Medical University were used to establish the NAFLD model&#46; All rats were acclimated for one week prior to experimentation according to a previous protocol published <a class="elsevierStyleCrossRef" href="#bib0335">&#91;28&#93;</a>&#46; Briefly&#44; two initial groups of rats were randomly separated&#46; The normal control &#40;NC&#41; group &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>13&#41; was fed chow containing 62&#37; carbohydrates&#44; 10&#37; fat&#44; and 28&#37; protein&#59; the HFD group &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>37&#41; was fed chow containing 34&#37; carbohydrates&#44; 52&#37; fat&#44; and 14&#37; protein&#46; Five rats from each group were randomly selected to confirm successful establishment of NAFLD after 12 weeks of feeding&#46; &#40;All animals received humane care according to the criteria outlined in the &#8220;Guide for the Care and Use of Laboratory Animals&#8221; prepared by the National Academy of Sciences and published by the National Institutes of Health&#46;&#41;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Rats in the HFD group were randomly subdivided into four groups&#58; HFD&#44; 50<span class="elsevierStyleHsp" style=""></span>L&#44; 100<span class="elsevierStyleHsp" style=""></span>L&#44; and 200<span class="elsevierStyleHsp" style=""></span>L &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8 in each group&#41;&#46; Rats in the HFD group were continually fed a HFD and were given 0&#46;5<span class="elsevierStyleHsp" style=""></span>ml&#47;kg of normal saline as needed&#46; Rats in the 50<span class="elsevierStyleHsp" style=""></span>L&#44; 100<span class="elsevierStyleHsp" style=""></span>L&#44; and 200<span class="elsevierStyleHsp" style=""></span>L groups continued to receive HFD with different doses of liraglutide &#40;L&#41; &#40;50&#44; 100&#44; or 200<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;kg&#41; &#40;Victoza&#44; Novo-Nordisk A&#47;S&#44; Denmark&#41;&#44; respectively&#46; The rats in the NC group &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8&#41; continued to receive normal chow and were injected with 0&#46;5<span class="elsevierStyleHsp" style=""></span>ml&#47;kg of normal saline&#46; Saline and liraglutide were injected subcutaneously at 8&#58;00<span class="elsevierStyleHsp" style=""></span>am and 8&#58;00<span class="elsevierStyleHsp" style=""></span>pm every day for 4 weeks&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;2</span><span class="elsevierStyleSectionTitle" id="sect0050">Cell culture and treatment</span><p id="par0035" class="elsevierStylePara elsevierViewall">HepG2 cells were cultured at 37<span class="elsevierStyleHsp" style=""></span>&#176;C in a humidified chamber with 5&#37; CO<span class="elsevierStyleInf">2</span> and maintained in Dulbecco&#39;s modified Eagle&#39;s medium &#40;DMEM&#44; Gibco&#41; containing 10&#37; heat-inactivated fetal bovine serum &#40;FBS&#44; Gibco&#41;&#46; There were a total of six cell culture groups&#58; Control group treated with serum-free bovine serum albumin &#40;BSA&#59; Sigma&#8211;Aldrich&#44; USA&#41; medium&#59; PA group treated with or without 400<span class="elsevierStyleHsp" style=""></span>M palmitate fatty acid &#40;PA&#41; for 24<span class="elsevierStyleHsp" style=""></span>h&#59; and experimental groups treated with 400<span class="elsevierStyleHsp" style=""></span>M PA and either 10&#44; 50&#44; l00&#44; or 500<span class="elsevierStyleHsp" style=""></span>nmol&#47;L liraglutide for 24<span class="elsevierStyleHsp" style=""></span>h&#44; respectively&#46; These cells were divided into four groups&#58; normal HepG2 cells &#40;BSA&#41;&#44; treated with PA &#40;PA&#41;&#44; treated with PA and liraglutide &#40;100G&#41;&#44; and Compound C for 30<span class="elsevierStyleHsp" style=""></span>min and then treated with PA and liraglutide &#40;100G<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>C&#41;&#46; Command C is an AMPK pathway inhibitor&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;3</span><span class="elsevierStyleSectionTitle" id="sect0055">Western blot analysis</span><p id="par0040" class="elsevierStylePara elsevierViewall">Liver specimens and whole-cell extracts were homogenized and centrifuged in RIPA buffer &#40;Beyotime Institute of Biotechnology&#44; China&#41; containing a protease inhibitor cocktail with 1<span class="elsevierStyleHsp" style=""></span>mmol&#47;L phenylmethanesulfonyl fluoride &#40;Beyotime&#41; on ice&#46; Protein lysates were quantified using the BCA assay as previous described <a class="elsevierStyleCrossRef" href="#bib0335">&#91;28&#93;</a> &#40;Pierce&#44; USA&#41;&#46; 50<span class="elsevierStyleHsp" style=""></span>&#956;g of protein for each sample were separated by 8&#8211;10&#37; SDS-PAGE and transferred to PVDF membranes &#40;Millipore&#44; USA&#41;&#46; The membranes were blocked with 5&#37; BSA and then incubated with primary antibodies against microtubule-associated protein LC3&#44; Beclin1&#44; AMPK&#44; phosphorylated &#40;p&#41;-AMPK&#44; TSC1&#44; mTOR&#44; and p-mTOR &#40;all of which were used at 1&#58;1000 and purchased from Cell Signaling Technology&#44; USA&#41; and GAPDH &#40;used at 1&#58;1000&#59; Santa Cruz&#44; CA&#44; USA&#41; at 4<span class="elsevierStyleHsp" style=""></span>&#176;C overnight&#46; The horseradish peroxidase-conjugated anti-rabbit&#44; anti-goat&#44; or anti-mouse secondary antibodies &#40;1&#58;5000&#44; all from Santa Cruz Biotechnology&#44; Inc&#46;&#41; were added at room temperature for 2<span class="elsevierStyleHsp" style=""></span>h after 3 washes &#40;10<span class="elsevierStyleHsp" style=""></span>min each&#41;&#46; The immunological complexes were visualized with Micro Chemi 4&#46;2 &#40;DNR Bio-Imaging Systems Ltd&#46;&#44; Jerusalem&#44; Israel&#41;&#46; Quantity One Software &#40;Bio-Rad&#44; USA&#41; was used to quantify the protein band intensity&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;4</span><span class="elsevierStyleSectionTitle" id="sect0060">Real-time RT-PCR</span><p id="par0045" class="elsevierStylePara elsevierViewall">Total RNA from the frozen liver specimens &#40;100<span class="elsevierStyleHsp" style=""></span>mg&#41; and cell cultures were isolated using Trizol reagent &#40;Takara Biotechnology Co&#46;&#44; Ltd&#46;&#41;&#46; The PrimeScriptTM RT reagent kit was used to synthesize cDNA &#40;Takara Biotechnology Co&#46;&#44; Ltd&#46;&#44; Dalian&#44; China&#41;&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">Real-time RT-PCR analysis was performed with a Thermal Cycler Dice Real Time detection System &#40;Takara Bio Inc&#46;&#44; Japan&#41; using the SYBR Premix Ex Taq II kit &#40;Tli RNaseH Plus&#41; &#40;Takara Biotechnology Co&#46;&#44; Ltd&#46;&#41;&#46; Gene-specific primers for GFAP and GAPDH were purchased from Takara Biotechnology Co&#46;&#44; Ltd&#46; The following PCR protocol was used for all genes&#58; reverse transcription step for 15<span class="elsevierStyleHsp" style=""></span>min at 37<span class="elsevierStyleHsp" style=""></span>&#176;C&#44; then denaturation at 85<span class="elsevierStyleHsp" style=""></span>&#176;C for 5<span class="elsevierStyleHsp" style=""></span>s&#44; 4<span class="elsevierStyleHsp" style=""></span>&#176;C for 7<span class="elsevierStyleHsp" style=""></span>min&#44; followed by an additional 40 cycles of amplification and quantification &#40;5<span class="elsevierStyleHsp" style=""></span>s at 95<span class="elsevierStyleHsp" style=""></span>&#176;C&#59; 30<span class="elsevierStyleHsp" style=""></span>s at 60<span class="elsevierStyleHsp" style=""></span>&#176;C&#59; 30<span class="elsevierStyleHsp" style=""></span>s at 60<span class="elsevierStyleHsp" style=""></span>&#176;C&#41;&#46; mRNA expression was normalized to GAPDH as a housekeeping gene&#46; The primers were designed &#40;Primer Premier 5&#46;0&#41; and synthesized &#40;Takara Biotechnology Co&#46;&#44; Ltd&#46; Dalian&#44; China&#41;&#46; For each gene&#44; the relative change of mRNA in the samples was calculated by subtracting GAPDH Ct values from Ct values for the gene of interest using the 2&#8722;&#916;&#916;Ct method&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;5</span><span class="elsevierStyleSectionTitle" id="sect0065">Electron microscopy</span><p id="par0055" class="elsevierStylePara elsevierViewall">For transmission electron microscopy &#40;TEM&#41;&#44; liver specimens were fixed with 2&#46;5&#37; glutaraldehyde in a 0&#46;1<span class="elsevierStyleHsp" style=""></span>M sodium cacodylate&#44; pH 7&#46;4&#44; buffer at 4<span class="elsevierStyleHsp" style=""></span>&#176;C and then minced into small &#40;1<span class="elsevierStyleHsp" style=""></span>mm<span class="elsevierStyleSup">3</span>&#41; fragments&#46; After washing with 0&#46;1<span class="elsevierStyleHsp" style=""></span>M phosphate buffered saline &#40;PBS&#41; three times for 15<span class="elsevierStyleHsp" style=""></span>min each&#44; the liver tissue samples were fixed in 1&#37; osmium tetroxide &#40;OSO<span class="elsevierStyleInf">4</span>&#41; for 1<span class="elsevierStyleHsp" style=""></span>h&#44; followed by washes in 0&#46;1<span class="elsevierStyleHsp" style=""></span>M PBS&#46; Liver tissues were gradually dehydrated in ethanol solutions of 20&#37;&#44; 50&#37;&#44; 70&#37; and 90&#37; and embedded in Epon 812 epoxy resin before ultrathin sectioning&#46; The ultrastructure of the sections was visualized using a JEM-1200EX electron microscope &#40;JEOL Co&#46;&#44; Japan&#41; in the TEM laboratory of China Medical University&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;6</span><span class="elsevierStyleSectionTitle" id="sect0070">Hematoxylin and eosin &#40;HE&#41; Staining</span><p id="par0060" class="elsevierStylePara elsevierViewall">The liver tissues were fixed at 5<span class="elsevierStyleHsp" style=""></span>mm from the edge of the right lobe of the liver and immersed in 4&#37; paraformaldehyde&#46; Then the tissues were dehydrated&#44; waxed&#44; embedded&#44; and sliced for HE staining&#46; Samples were dewaxed&#44; benzenes were removed&#44; hydrated&#44; hematoxylin stained&#44; washed&#44; eosin stained&#44; dehydrated&#44; and imaged&#46; According to the 2010 guidelines for the diagnosis and treatment of NLFD liver histopathological sections were scored based on the NAS system &#40;0 to 8 points&#41;&#58; &#40;1&#41; hepatocellular steatosis&#58; 0 points &#40;&#60;5&#37;&#41;&#59; 1 point &#40;5&#8211;33&#37;&#41;&#59; 2 points &#40;34&#8211;66&#37;&#41;&#59; 3 points &#40;&#62;66&#37;&#41;&#59; &#40;2&#41; Inflammation within the lobules &#40;inflammatory necrosis at 20-fold microscopy&#41;&#58; 0 points &#40;none&#41;&#44; 1 point &#40;&#60;2&#41;&#44; 2 points &#40;2&#8211;4&#41;&#44; 3 points &#40;&#62;4&#41;&#59; &#40;3&#41; liver cell ballooning&#58; 0 points&#44; no&#59; 1 point&#44; rare&#59; 2 points&#44; more common&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;7</span><span class="elsevierStyleSectionTitle" id="sect0075">Statistical analysis</span><p id="par0065" class="elsevierStylePara elsevierViewall">All data are expressed as the mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>standard deviation &#40;SD&#41; and calculated with one-way analysis of variance &#40;ANOVA&#41; followed by a Newman&#8211;Keuls post-hoc test &#40;SPSS 17&#46;0&#41;&#46; Results of comparisons were considered significantly different if the <span class="elsevierStyleItalic">p</span> value was<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#46;</p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3</span><span class="elsevierStyleSectionTitle" id="sect0080">Results</span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;1</span><span class="elsevierStyleSectionTitle" id="sect0085">Liraglutide improves hepatic histology during NAFLD development</span><p id="par0070" class="elsevierStylePara elsevierViewall">After 16 weeks of HFD or normal chow diet we examined the histological features of the livers from NAFLD and NC mice&#46; The liver surfaces were greyish yellow and the edges were blunt and thick in the HFD group compared to the NC group&#44; in which the livers were bright red with sharp edges&#46; Liraglutide dose-dependently ameliorated the pathological hepatic histology in the HFD group &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>A&#8211;E&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">As shown in <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>A&#8211;E&#44; liraglutide improved the hepatic histology by significantly reducing both fatty droplets and inflammatory foci number&#46; NAS quantification of liver sections further confirmed the beneficial effects of liraglutide treatment on hepatic histology &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Compared to the NC rats&#44; the HFD rats had more hepatocellular steatosis &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">0&#46;05</span>&#41;&#44; but liraglutide dose-dependently and significantly decreased steatosis&#44; inflammation&#44; and ballooning in the HFD group compared to the NC group &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">0&#46;05</span>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;2</span><span class="elsevierStyleSectionTitle" id="sect0090">Liraglutide improves autophagy in the NAFLD rat model</span><p id="par0080" class="elsevierStylePara elsevierViewall">We used electron microscopy to measure autophagosomes in each group&#46; We found that the number of autophagosomes in the HFD group was significantly lower compared to the NC group&#46; Liraglutide treatment dose-dependently increased the number of autophagocytic bodies in the HFD group compared to the NC group &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>A and B&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0085" class="elsevierStylePara elsevierViewall">To further determine whether liraglutide improves autophagy in HFD-induced NAFLD rats&#44; we measured the expression of autophagy-related proteins&#44; LC3&#44; Beclin1 and Atg7&#44; in liver tissues&#46; We found that LC3&#44; Beclin1 and Atg7 mRNA levels and protein expression were significantly reduced in the HFD group and that liraglutide treatment dramatically increased expression of these autophagy markers &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>A&#8211;F&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;3</span><span class="elsevierStyleSectionTitle" id="sect0095">Liraglutide improves autophagy in HepG2 cell <span class="elsevierStyleItalic">in vitro</span></span><p id="par0090" class="elsevierStylePara elsevierViewall">We measured mRNA and protein expression of the autophagy-related proteins&#44; LC3&#44; Beclin1 and Atg7&#44; in HepG2 cells following PA treatment&#46; In the PA group&#44; mRNA and protein expression of LC3&#44; Beclin1 and Atg7 were significantly lower compared to the BSA group &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">0&#46;01</span>&#41;&#46; However&#44; liraglutide dose-dependently increased the mRNA and protein levels of LC3&#44; Beclin1 and Atg7 relative to the PA group &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">0&#46;01</span>&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a>A&#8211;F&#41;&#46;</p><elsevierMultimedia ident="fig0025"></elsevierMultimedia></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;4</span><span class="elsevierStyleSectionTitle" id="sect0100">The effect of liraglutide on autophagy in HepG2 cells following AMPK pathway inhibition</span><p id="par0095" class="elsevierStylePara elsevierViewall">To investigate whether the AMPK pathway was involved in liraglutide-mediated improvement of autophagy after PA treatment&#44; we measured protein levels of LC3&#44; Beclin1 and Atg7 in HepG2 cells&#46; The results showed that the levels of LC3&#44; Beclin1 and Atg7 were significantly higher in the liraglutide intervention group &#40;100G group&#41; compared to the PA group &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">0&#46;01</span>&#41;&#46; However&#44; LC3&#44; Beclin1 and Atg7 levels were significantly lower in the inhibition group &#40;100G&#43;C&#41; containing Compound C&#44; PA &#40;400<span class="elsevierStyleHsp" style=""></span>mmol&#47;L&#41; and liraglutide &#40;100<span class="elsevierStyleHsp" style=""></span>nmol&#47;L&#41;&#44; compared to the 100G group &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">0&#46;01</span>&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0030">Fig&#46; 6</a>A&#8211;C&#41;&#46;</p><elsevierMultimedia ident="fig0030"></elsevierMultimedia></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;5</span><span class="elsevierStyleSectionTitle" id="sect0105">Effects of liraglutide on AMPK pathway-associated proteins following AMPK pathway inhibition</span><p id="par0100" class="elsevierStylePara elsevierViewall">We measured expression of AMPK pathway-associated proteins to confirm that liraglutide-mediated autophagy induced by PA could be reversed by inhibiting the AMPK pathway&#46; As shown in <a class="elsevierStyleCrossRef" href="#fig0030">Fig&#46; 6</a>&#44; the levels of p-AMPK&#47;AMPK&#44; TSC1&#44; p-mTOR&#47;mTOR were decreased &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#41; in the PA group &#40;400<span class="elsevierStyleHsp" style=""></span>&#956;mol&#47;L PA&#41; compared to the control group &#40;BSA group&#41;&#46; Furthermore&#44; the levels of p-AMPK&#47;AMPK&#44; TSC1&#44; and p-mTOR&#47;mTOR were increased in the liraglutide intervention group &#40;100G group&#41; compared to the PA group &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">0&#46;05</span>&#41;&#46; The levels of p-AMPK&#47;AMPK&#44; TSC1&#44; p-mTOR&#47;mTOR were significantly lower than those in the 100G group compared to the inhibition group &#40;100 G&#43;C&#41; containing Compound C&#44; PA &#40;400<span class="elsevierStyleHsp" style=""></span>&#956;mol&#47;L&#41;&#44; and liraglutide &#40;100<span class="elsevierStyleHsp" style=""></span>nmol&#47;L&#41; &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0035">Fig&#46; 7</a>A&#8211;C&#41;&#46;</p><elsevierMultimedia ident="fig0035"></elsevierMultimedia></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">4</span><span class="elsevierStyleSectionTitle" id="sect0110">Discussion</span><p id="par0105" class="elsevierStylePara elsevierViewall">The prevalence of NAFLD has increased worldwide&#44; affecting both adults and children&#46; Liraglutide&#44; a GLP-1 analog&#44; has been reported to decrease lipid deposition and inflammation in hepatocytes <a class="elsevierStyleCrossRefs" href="#bib0340">&#91;29&#44;30&#93;</a>&#46; However&#44; few studies have investigated whether liraglutide can improve hepatic lipid accumulation in NAFLD&#46; In the current study&#44; we used an established rat model of HFD-induced NAFLD and demonstrated that liraglutide significantly decreased the number of autophagosomes&#46; Liraglutide treatment dose-dependently improved autophagy&#44; which was confirmed by measuring expression of autophagy-related proteins <span class="elsevierStyleItalic">in</span><span class="elsevierStyleItalic">vivo</span> and <span class="elsevierStyleItalic">in vitro</span>&#46; More importantly&#44; the AMPK pathway inhibitor&#44; Compound C&#44; reversed liraglutide&#39;s effects on autophagy following PA treatment <span class="elsevierStyleItalic">in vitro</span>&#44; which suggests that liraglutide-induced autophagy is mediated by the AMPK signaling pathway&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Autophagy is an intracellular pathway that maintains normal cellular function by promoting turnover of long-lived proteins <a class="elsevierStyleCrossRef" href="#bib0350">&#91;31&#93;</a>&#46; Studies have demonstrated that enhanced autophagy can rescue pancreatic &#946;-cells from glucotoxicity&#44; and inhibition of autophagy augments caspase-3 activation <a class="elsevierStyleCrossRef" href="#bib0355">&#91;32&#93;</a>&#44; suggesting that autophagy might protect against Type 2 Diabetes&#46; Previous evidence indicated that autophagy is suppressed in the presence of hyper-insulinemia induced by HFD in mice <a class="elsevierStyleCrossRef" href="#bib0360">&#91;33&#93;</a>&#44; which was consistent with our results&#59; however&#44; we note that we used a different animal model in our study&#46; Our results indicate that autophagy was significantly decreased in the NAFLD rat model&#44; since the autophagy-related proteins&#44; LC3&#44; Beclin1 and Atg7&#44; were significantly reduced at both the mRNA and protein levels&#46; We also noticed that autophagy-related protein levels were decreased in palmitate-induced lipotoxicity in HepG2 cells <span class="elsevierStyleItalic">in vitro</span>&#44; which mimics the pathogenic features of the NAFLD model <span class="elsevierStyleItalic">in vivo</span>&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Liraglutide&#44; a GLP-1 analog&#44; regulates &#946;-cell mass via multiple pathways <a class="elsevierStyleCrossRefs" href="#bib0365">&#91;34&#8211;36&#93;</a>&#46; Liraglutide was proven to decrease lipid accumulation in the steatotic LO2 cell model <a class="elsevierStyleCrossRef" href="#bib0380">&#91;37&#93;</a> and protect pancreatic &#946;-cells from high glucose by enhancing autophagy via AMPK <a class="elsevierStyleCrossRef" href="#bib0325">&#91;26&#93;</a>&#46; It is also known that GLP-1 exerts protective effects on hepatic steatosis <a class="elsevierStyleCrossRef" href="#bib0385">&#91;38&#93;</a>&#46; In the present study&#44; we found that the general appearance&#44; histopathological changes&#44; and the number of autophagic bodies in the livers of NAFLD rats improved after liraglutide treatment&#46; Further evidence showed that liraglutide does-dependently increased the expression of autophagy-related proteins in rats fed a HFD and in HepG2 cells treated with PA&#46; These results suggest that GLP-1 ameliorates HFD induced NAFLD by activating autophagy&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Existing research shows that the AMPK&#47;mTOR pathway regulates downstream signaling to trigger autophagy <a class="elsevierStyleCrossRef" href="#bib0390">&#91;39&#93;</a>&#46; AMPK could negatively affect liraglutide-induced increases in cell viability and autophagy to protect insulin-1 pancreatic &#946;-cells from glucotoxicity in rats <a class="elsevierStyleCrossRef" href="#bib0330">&#91;27&#93;</a>&#46; In addition&#44; AMPK&#47;mTOR signaling was involved in hepatic lipid metabolism induced by GLP-1 <a class="elsevierStyleCrossRef" href="#bib0325">&#91;26&#93;</a>&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Our data revealed that Command C&#44; an AMPK pathway inhibitor&#44; reversed the enhanced autophagy induced by liraglutide in HepG2 cells treated with PA&#44; which suggests that liraglutide intervention activates AMPK and up-regulates autophagy&#46; Thus&#44; we conclude that the AMPK pathway plays an important role in regulating autophagy induced by liraglutide&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">In conclusion&#44; the current study demonstrates that liraglutide can improve hepatic steatosis via activating the AMPK pathway&#46; These data suggest that GLP-1 may play a protective role in several models of NAFLD and that modulation of AMPK could be a potential target for lipid metabolic disorders&#46;<span class="elsevierStyleDefList"><span class="elsevierStyleSectionTitle" id="sect0115">Abbreviations</span><span class="elsevierStyleDefTerm">AMPK</span><span class="elsevierStyleDefDescription"><p id="par0135" class="elsevierStylePara elsevierViewall">adenosine 5&#8242;-monophosphate &#40;AMP&#41;-activated protein kinase</p></span><span class="elsevierStyleDefTerm">Atg7</span><span class="elsevierStyleDefDescription"><p id="par0140" class="elsevierStylePara elsevierViewall">autophagy related gene 7</p></span><span class="elsevierStyleDefTerm">Beclin1</span><span class="elsevierStyleDefDescription"><p id="par0145" class="elsevierStylePara elsevierViewall">heterozygous disruption of beclin1</p></span><span class="elsevierStyleDefTerm">cAMP</span><span class="elsevierStyleDefDescription"><p id="par0150" class="elsevierStylePara elsevierViewall">cyclic adenosine monophosphate</p></span><span class="elsevierStyleDefTerm">GLP-1</span><span class="elsevierStyleDefDescription"><p id="par0155" class="elsevierStylePara elsevierViewall">glucagon-like peptide-1</p></span><span class="elsevierStyleDefTerm">LC3</span><span class="elsevierStyleDefDescription"><p id="par0160" class="elsevierStylePara elsevierViewall">micro-tubule-associated protein1 light chain 3</p></span><span class="elsevierStyleDefTerm">mTOR</span><span class="elsevierStyleDefDescription"><p id="par0165" class="elsevierStylePara elsevierViewall">the mammalian target of rapamycin</p></span><span class="elsevierStyleDefTerm">NAFLD</span><span class="elsevierStyleDefDescription"><p id="par0170" class="elsevierStylePara elsevierViewall">nonalcoholic fatty liver disease</p></span><span class="elsevierStyleDefTerm">PA</span><span class="elsevierStyleDefDescription"><p id="par0175" class="elsevierStylePara elsevierViewall">palmitate</p></span><span class="elsevierStyleDefTerm">T2DM</span><span class="elsevierStyleDefDescription"><p id="par0180" class="elsevierStylePara elsevierViewall">type 2 diabetes mellitus</p></span><span class="elsevierStyleDefTerm">TSC1</span><span class="elsevierStyleDefDescription"><p id="par0185" class="elsevierStylePara elsevierViewall">tuberous sclerosis-1</p></span></span></p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Author&#39;s contribution</span><p id="par0190" class="elsevierStylePara elsevierViewall">Description of author roles in manuscript creation&#58; Jian Du designed the experiment&#46; Yini He&#44; Na Ao and Jing Yang performed the performed experiments&#44; Xiaochen Wang and Shi Jin processed the data&#44; Yini He wrote the paper&#44; and Jian Du modified the paper&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Funding</span><p id="par0195" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleGrantSponsor" id="gs1">The Science and Technology Agency of Liao Ning</span> &#40;<span class="elsevierStyleGrantNumber" refid="gs1">20170520272</span>&#41;&#59; <span class="elsevierStyleGrantSponsor" id="gs2">The Hall Education of Liaoning</span> &#40;<span class="elsevierStyleGrantNumber" refid="gs2">L2015567</span>&#41; &#40;LQNK201715&#41;&#46;</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Conflict of interest</span><p id="par0200" class="elsevierStylePara elsevierViewall">All authors declare no conflicts of interest&#46;</p></span></span>"
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              "titulo" => "Western blot analysis"
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              "titulo" => "Real-time RT-PCR"
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          "titulo" => "Results"
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              "titulo" => "Liraglutide improves hepatic histology during NAFLD development"
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              "titulo" => "Liraglutide improves autophagy in the NAFLD rat model"
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              "titulo" => "Liraglutide improves autophagy in HepG2 cell in vitro"
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              "titulo" => "The effect of liraglutide on autophagy in HepG2 cells following AMPK pathway inhibition"
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              "titulo" => "Effects of liraglutide on AMPK pathway-associated proteins following AMPK pathway inhibition"
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    "fechaRecibido" => "2019-02-25"
    "fechaAceptado" => "2019-06-25"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction and objectives</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The incidence of non-alcoholic fatty liver disease &#40;NAFLD&#41; is increasing&#46; Previous studies indicated that Liraglutide&#44; glucagon-like peptide-1 analogue&#44; could regulate glucose homeostasis as a valuable treatment for Type 2 Diabetes&#46; However&#44; the precise effect of Liraglutide on NAFLD model in rats and the mechanism remains unknown&#46; In this study&#44; we investigated the molecular mechanism by which Liraglutide ameliorates hepatic steatosis in a high-fat diet &#40;HFD&#41;-induced rat model of NAFLD in vivo and in vitro&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Materials and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">NALFD rat models and hepatocyte steatosis in HepG2 cells were induced by HFD and palmitate fatty acid treatment&#44; respectively&#46; AMPK inhibitor&#44; Compound C was added in HepG2 cells&#46; Autophagy-related proteins LC3&#44; Beclin1 and Atg7&#44; and AMPK pathway-associated proteins were evaluated by Western blot and RT-PCR&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Liraglutide enhanced autophagy as showed by the increased expression of the autophagy markers LC3&#44; Beclin1 and Atg7 in HFD rats and HepG2 cells treated with palmitate fatty acid&#46; In vitro&#44; The AMPK inhibitor exhibited an inhibitory effect on Liraglutide-induced autophagy enhancement with the deceased expression of LC3&#44; Beclin1 and Atg7&#46; Additionally&#44; Liraglutide treatment elevated AMPK levels and TSC1&#44; decreased p-mTOR expression&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Liraglutide could upregulate autophagy to decrease lipid over-accumulation via the AMPK&#47;mTOR pathway&#46;</p></span>"
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          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Histopathological changes in rat livers 16 weeks after HFD&#46; A&#46; Histopathological changes &#40;&#215; 200&#41;&#59; B&#46; Rat liver histopathological NAS scores&#59; C&#46; 50<span class="elsevierStyleHsp" style=""></span>L group&#58; low dose liraglutide intervention group &#40;50<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;kg&#41;&#44; D&#46; 100<span class="elsevierStyleHsp" style=""></span>L group&#58; middle dose liraglutide intervention group &#40;100<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;kg&#41;&#44; E&#46; 200<span class="elsevierStyleHsp" style=""></span>L group&#58; high-dose liraglutide intervention group &#40;200<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;kg&#41;&#46;</p>"
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          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Ultrastructure of hepatocytes observed by electron microscopy&#46; A&#46; NC group&#44; B&#46; HF group&#44; C&#46; 50<span class="elsevierStyleHsp" style=""></span>L group&#58; low dose liraglutide intervention group &#40;50<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;kg&#41;&#44; D&#46; 100<span class="elsevierStyleHsp" style=""></span>L group&#58; middle dose liraglutide intervention group &#40;100<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;kg&#41;&#44; E&#46; 200<span class="elsevierStyleHsp" style=""></span>L group&#58; high-dose liraglutide intervention group &#40;200<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;kg&#41;&#46; N&#44; nucleus&#59; LD&#44; lipid droplet&#59; &#8594;&#44; autophagy body&#46;</p>"
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          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Liraglutide reversed the decrease in autophagy related proteins in HFD-induce NAFLD rats&#46; A and B&#46; LC3II mRNA expression and LC3II&#47;LC3I protein were assessed by real-time RT-PCR and Western blot&#44; respectively&#46; C and D&#46; Beclin1 mRNA and protein expression were detected by real-time RT-PCR and Western blot&#44; respectively&#46; E and F&#46; Atg7 mRNA and protein expression were measured by real-time RT-PCR and Western blot&#44; respectively&#46;</p>"
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Liraglutide reversed the decrease in autophagy related proteins in HepG2 cells&#46; A and B&#46; LC3II mRNA and protein expression were assessed by real-time RT-PCR and Western blot&#44; respectively&#46; C and D&#46; Beclin1 mRNA and protein expression were detected by real-time RT-PCR and Western blot&#44; respectively&#46; E and F&#46; Atg7 mRNA and protein expression were measured by real-time RT-PCR and Western blot&#44; respectively&#46;</p>"
        ]
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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">The effect of liraglutide on autophagy in HepG2 cells in the presence of the AMPK pathway inhibitor&#46; A&#46; Expression of LC3II&#47;LC3I detected by Western blot with or without the AMPK pathway inhibitor&#46; B&#46; Expression of Beclin1 detected by Western blot with or without the AMPK pathway inhibitor&#46; C&#46; Expression of Atg7 detected by Western blot with or without the AMPK pathway inhibitor&#46;</p>"
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        "identificador" => "fig0035"
        "etiqueta" => "Fig&#46; 7"
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        "mostrarFloat" => true
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          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Effects of liraglutide on AMPK pathway-associated proteins in the presence of the AMPK pathway inhibitor&#46; A&#46; Expression of p-AMPK&#47;AMPK detected by Western blot&#46; B&#46; Expression of TSC1 detected by Western blot&#46; C&#46; Expression of p-mTOR&#47;mTOR detected by Western blot&#46;</p>"
        ]
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                  \t\t\t\t">NC&nbsp;\t\t\t\t\t\t\n
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            1 => array:3 [
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">compared to HF group&#44;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05</p>"
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          "en" => "<p id="spar4060" class="elsevierStyleSimplePara elsevierViewall">The NAS scores of hepatic pathological sections after 16 weeks of HFD</p>"
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      "titulo" => "References"
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        0 => array:2 [
          "identificador" => "bibs0015"
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              "identificador" => "bib0200"
              "etiqueta" => "&#91;1&#93;"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Epidemiology and risk factors of nonalcoholic fatty liver disease &#40;NAFLD&#41; and nonalcoholic steatohepatitis &#40;NASH&#41;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "R&#46; Tateishi"
                            1 => "K&#46; Koike"
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                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Nihon Shokakibyo Gakkai Zasshi"
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                        "volumen" => "114"
                        "numero" => "5"
                        "paginaInicial" => "813"
                        "paginaFinal" => "818"
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            1 => array:3 [
              "identificador" => "bib0205"
              "etiqueta" => "&#91;2&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The epidemiology of non-alcoholic fatty liver disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "S&#46; Bellentani"
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                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/liv.13299"
                      "Revista" => array:7 [
                        "tituloSerie" => "Liver Int"
                        "fecha" => "2017"
                        "volumen" => "37"
                        "numero" => "Suppl&#46; 1"
                        "paginaInicial" => "81"
                        "paginaFinal" => "84"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28052624"
                            "web" => "Medline"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The transcriptomic signature of disease development and progression of nonalcoholic fatty liver disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46; Cazanave"
                            1 => "A&#46; Podtelezhnikov"
                            2 => "K&#46; Jensen"
                            3 => "M&#46; Seneshaw"
                            4 => "D&#46;P&#46; Kumar"
                            5 => "H&#46;K&#46; Min"
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                    0 => array:2 [
                      "doi" => "10.1038/s41598-017-17370-6"
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                        "tituloSerie" => "Sci Rep"
                        "fecha" => "2017"
                        "volumen" => "7"
                        "numero" => "1"
                        "paginaInicial" => "17193"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29222421"
                            "web" => "Medline"
                          ]
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              "identificador" => "bib0215"
              "etiqueta" => "&#91;4&#93;"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Genetic and epigenetic regulation in nonalcoholic fatty liver disease &#40;NAFLD&#41;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "J&#46;A&#46; Del Campo"
                            1 => "R&#46; Gallego-Duran"
                            2 => "P&#46; Gallego"
                            3 => "L&#46; Grande"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3390/ijms19113682"
                      "Revista" => array:6 [
                        "tituloSerie" => "Int J Mol Sci"
                        "fecha" => "2018"
                        "volumen" => "19"
                        "numero" => "3&#46;"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30469338"
                            "web" => "Medline"
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                        "itemHostRev" => array:3 [
                          "pii" => "S2211034817300664"
                          "estado" => "S300"
                          "issn" => "22110348"
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                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The relationship of nonalcoholic fatty liver disease and metabolic syndrome for colonoscopy colorectal neoplasm"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46; Pan"
                            1 => "W&#46; Hong"
                            2 => "W&#46; Wu"
                            3 => "Q&#46; Chen"
                            4 => "Q&#46; Zhao"
                            5 => "J&#46; Wu"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Medicine &#40;Baltimore&#41;"
                        "fecha" => "2017"
                        "volumen" => "96"
                        "numero" => "2"
                        "paginaInicial" => "e5809"
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                      "titulo" => "Genetic variants associated with obesity and insulin resistance in hispanic boys with nonalcoholic fatty liver disease"
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Article information

ISSN: 16652681
Original language: English

DOI:10.1016/j.aohep.2019.06.023

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Year/Month	Html	Pdf	Total

2024 November	6	1	7
2024 October	36	4	40
2024 September	40	3	43
2024 August	29	2	31
2024 July	54	5	59
2024 June	41	5	46
2024 May	47	8	55
2024 April	54	2	56
2024 March	48	6	54
2024 February	50	4	54
2024 January	58	5	63
2023 December	52	9	61
2023 November	55	4	59
2023 October	62	4	66
2023 September	22	3	25
2023 August	50	8	58
2023 July	27	4	31
2023 June	34	6	40
2023 May	59	4	63
2023 April	60	3	63
2023 March	54	9	63
2023 February	38	4	42
2023 January	21	6	27
2022 December	19	11	30
2022 November	24	11	35
2022 October	21	7	28
2022 September	23	12	35
2022 August	11	10	21
2022 July	25	8	33
2022 June	17	7	24
2022 May	38	16	54
2022 April	12	7	19
2022 March	44	8	52
2022 February	29	8	37
2022 January	53	10	63
2021 December	26	9	35
2021 November	17	10	27
2021 October	37	10	47
2021 September	26	9	35
2021 August	54	4	58
2021 July	25	9	34
2021 June	11	9	20
2021 May	18	5	23
2021 April	54	17	71
2021 March	31	21	52
2021 February	20	4	24
2021 January	29	11	40
2020 December	32	6	38
2020 November	32	6	38
2020 October	26	5	31
2020 September	21	12	33
2020 August	22	9	31
2020 July	41	24	65
2020 June	22	2	24
2020 May	25	10	35
2020 April	32	5	37
2020 March	72	14	86
2020 February	74	12	86
2020 January	50	18	68
2019 December	16	13	29
2019 November	5	8	13

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