Natural Extracts as Modifiers of Intracellular Lipid Handling
Rosellina Margherita Mancina, Piero Pingitore
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1 Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden
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Adipose tissue-derived factors can promote the progression of NAFLD towards severe histological stages (NASH-fibrosis and NASHcirrhosis). This effect can be modulated by the release of adipokines that directly trigger an inflammatory response in the liver tissue or indirectly modulate related phenotypes, such as insulin resistance (up-arrows). Metabolically dysfunctional adipose tissue, which is often infiltrated by macrophages and crown-like histological structures, may also show impaired production of anti-inflammatory adipokines, which may favor NAFLD progression into aggressive phenotypes by preventing its protective effects on the liver tissue (down-arrows). SFRP5: secreted frizzled-related protein 5. UCP1: uncoupling protein 1. FGF21: fibroblast growth factor 21. TNF a: tumor necrosis factor a. IL1 and IL6: interleukin 1 and 6. MCP-1: mono-cyte chemotactic protien-1.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Silvia Sookoian, Carlos J. Pirola" "autores" => array:2 [ 0 => array:2 [ "nombre" => "Silvia" "apellidos" => "Sookoian" ] 1 => array:2 [ "nombre" => "Carlos J." "apellidos" => "Pirola" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1665268119301498?idApp=UINPBA00004N" "url" => "/16652681/0000001700000002/v1_201905140709/S1665268119301498/v1_201905140709/en/main.assets" ] "en" => array:12 [ "idiomaDefecto" => true "titulo" => "Natural Extracts as Modifiers of Intracellular Lipid Handling" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "180" "paginaFinal" => "181" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Rosellina Margherita Mancina, Piero Pingitore" "autores" => array:2 [ 0 => array:2 [ "nombre" => "Rosellina Margherita" "apellidos" => "Mancina" ] 1 => array:4 [ "nombre" => "Piero" "apellidos" => "Pingitore" "email" => array:1 [ 0 => "piero.pingitore@wlab.gu.se" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:1 [ 0 => array:3 [ "entidad" => "Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden" "etiqueta" => "1" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "*" "correspondencia" => "Corresponding author." ] ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="s0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0005">Article commented</span><p id="p0005" class="elsevierStylePara elsevierViewall">Rojas A, Gallego P, Gil-Gómez A, Muñoz-Hernández R, Rojas L, Maldonado R, Gallego R, <span class="elsevierStyleItalic">et al.</span></p><p id="p0010" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Natural extracts abolished lipid accumulation in cells harbouring non favourable PNPLA3 genotype.</span></p><p id="p0015" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Ann Hepatol</span> 2018.</p><p id="p0020" class="elsevierStylePara elsevierViewall">Non-alcoholic fatty liver disease (NAFLD) is a spectrum of conditions ranging from simple liver fat accumulation to inflammation and fibrosis, and ultimately to cirrhosis and liver cancer. NAFLD prevalence is increasing worldwide and it is expected to be the main reason for liver transplantation in the next decade. Although NAFLD in its early stages can be resolved by dietary modifications and lifestyle changes (weight loss),<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> liver transplantation is the only existing treatment for the later stages of the disease. There is no drug approved as a specific treatment against NAFLD although vitamin E has shown to reduce NAFLD with a modest effect.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Based on antioxidant effects, natural compounds including resveratrol, quercetin and anthocyanin have been proposed as treatment against NAFLD.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="p0025" class="elsevierStylePara elsevierViewall">In this edition of <span class="elsevierStyleItalic">Annals of Hepatology</span>, Rojas, <span class="elsevierStyleItalic">et al.</span> examined the effect of quercetin and natural extracts from mushroom and artichoke, on reducing intracellular neutral lipid content in human hepatic cells. Specifically, Huh7.5 homozygous for <span class="elsevierStyleItalic">Patatin-like-phospholipase domain-containing 3 (PNPLA3)</span> I148M (rs738409) variant were incubated with oleic acid to increase intracellular neutral fat. Cells were subsequently treated with quercetin or with natural extracts from mushroom or artichoke, and lipid droplet content and size were measured by fluorescence microscopy. Authors found that quercetin reduces both lipid droplet content and size; aqueous extracts from mushroom and artichoke had similar effects. Next, to understand the mechanism behind the reduction of intracellular neutral fat content, authors measured the expression levels of genes involved in lipogenesis <span class="elsevierStyleItalic">(SREBP-1c, PPAR</span> γ<span class="elsevierStyleItalic">, ACAT1, FASN, DGAT1</span>, and <span class="elsevierStyleItalic">DGAT2)</span>, lipolysis <span class="elsevierStyleItalic">(PPAR</span>α), and lipid secretion <span class="elsevierStyleItalic">(MTTP, APOB</span>, and <span class="elsevierStyleItalic">APOE).</span></p><p id="p0030" class="elsevierStylePara elsevierViewall">The main finding of this study is that quercetin decreases de novo lipogenesis and increases lipolysis in human hepatocytes. In particular, quercetin treatment decreases the expression of <span class="elsevierStyleItalic">SREBP-1c</span> and increases the expression of <span class="elsevierStyleItalic">PPARa.</span> A similar trend was found with the artichoke extract. Additionally, in this <span class="elsevierStyleItalic">in vitro</span> model of steatosis, quercetin down-regulates genes involved in very low density lipoproteins (VLDL) secretion.</p><p id="p0035" class="elsevierStylePara elsevierViewall">A caveat of this study is that Huh7.5 cells are homozygous mutant for the <span class="elsevierStyleItalic">PNPLA3</span> (rs738409) I148M variant. The <span class="elsevierStyleItalic">PNPLA3</span> I148M represents the most widely replicated genetic variant associated with the entire spectrum of liver disease.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a>,<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a><span class="elsevierStyleItalic">PNPLA3</span> is a membrane-bound protein highly expressed in hepatocytes and hepatic stellate cells. It is a lipase<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> involved in hepatic triglycerides<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> and retinol metabolism,<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a>,<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> and the I148M substitution is a loss of function of the lipase activity. Importantly, in humans the I148M is associated with lower <span class="elsevierStyleItalic">de novo</span> lipogenesis and lower expression of the lipogenic transcription factor <span class="elsevierStyleItalic">SREBP-1c</span> despite a substantial increased hepatic fat content.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><p id="p0040" class="elsevierStylePara elsevierViewall">The importance of this study resides in using cells homozygous for the main NAFLD risk gene variant. It would be interesting to know whether the same effect would be found in the same cells with reversion of the <span class="elsevierStyleItalic">PNPLA3</span> gene to its wild type form. If this would not be the case, this study reinforces the concept of “one diet does not fit all”.</p><p id="p0045" class="elsevierStylePara elsevierViewall">In conclusion, the study by Rojas, <span class="elsevierStyleItalic">et al.</span> strengthens the role of quercetin in reducing intracellular fat content in NAFLD, and it helps to understand the molecular mechanisms behind this reduction.</p><p id="p0050" class="elsevierStylePara elsevierViewall">Further studies are needed to confirm and understand the effect of artichoke and mushroom extracts in other immortalized or primary hepatic cells and <span class="elsevierStyleItalic">in vivo.</span> Moreover, as the authors stated, it would be interesting to test the specific effect of each single compound included in the aqueous extracts.</p></span><span id="s0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0010">DISCLOSURES</span><p id="p0055" class="elsevierStylePara elsevierViewall">No disclosures.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:3 [ 0 => array:2 [ "identificador" => "s0005" "titulo" => "Article commented" ] 1 => array:2 [ "identificador" => "s0010" "titulo" => "DISCLOSURES" ] 2 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2018-01-24" "fechaAceptado" => "2018-01-25" "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bs0010" "bibliografiaReferencia" => array:10 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1." 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