Article

The Association of Genetic Variability in Patatin-Like Phospholipase Domain-Containing Protein 3 (PNPLA3) with Histological Severity of Nonalcoholic Fatty Liver Disease

Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-1800, USA.
Hepatology (Impact Factor: 11.19). 09/2010; 52(3):894-903. DOI: 10.1002/hep.23759
Source: PubMed

ABSTRACT Genome-wide association studies identified single-nucleotide polymorphisms (SNPs) that are associated with increased hepatic fat or elevated liver enzymes, presumably reflecting nonalcoholic fatty liver disease (NAFLD). To investigate whether these SNPs are associated with histological severity of NAFLD, 1117 (894 adults/223 children) individuals enrolled in the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network and National Institutes of Health Clinical Center studies with histologically confirmed NAFLD were genotyped for six SNPs that are associated with hepatic fat or liver enzymes in genome-wide association studies. In adults, three SNPs on chromosome 22 showed associations with histological parameters of NASH. After adjustment for age, sex, diabetes, and alcohol consumption, the minor allele of rs738409 C/G, a nonsynonymous coding SNP in the patatin-like phospholipase domain-containing protein 3 (PNPLA3) (adiponutrin) gene encoding an Ile148Met change, was associated with steatosis (P = 0.03), portal inflammation (P = 2.5 x 10(-4)), lobular inflammation (P = 0.005), Mallory-Denk bodies (P = 0.015), NAFLD activity score (NAS, P = 0.004), and fibrosis (P = 7.7 x 10(-6)). Two other SNPs in the same region demonstrated similar associations. Three SNPs on chromosome 10 near the CHUK (conserved helix-loop-helix ubiquitous kinase) gene were independently associated with fibrosis (P = 0.010). In children, no SNP was associated with histological severity. However, the rs738409 G allele was associated with younger age at the time of biopsy in multivariate analysis (P = 0.045). CONCLUSION: In this large cohort of histologically proven NAFLD, we confirm the association of the rs738409 G allele with steatosis and describe its association with histological severity. In pediatric patients, the high-risk rs738409 G allele is associated with an earlier presentation of disease. We also describe a hitherto unknown association between SNPs at a chromosome 10 locus and the severity of NASH fibrosis.

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    ABSTRACT: Numerous experimental, clinical and epidemiological studies show that exposure to environmental contaminants may disrupt endocrine and metabolic functions of our organism. This would contribute to the development of obesity and associated metabolic disorders such as nonalcoholic hepatic steatosis, characterized by an excessive accumulation of triglycerides in the liver, which may lead to more severe forms of NAFLD (Non-Alcoholic Fatty Liver Diseases) such as inflammation, fibrosis, cirrhosis and hepatocellular carcinoma. In this work, in vivo studies have highlighted that chronic exposure to the xenoestrogen BPA, widely used in plastic food packaging industry, affects hepatic energy metabolism. It promotes the storage of triglycerides and cholesterol ester in the liver, in association with the induction of the hepatic transcriptome, more particularly of genes involved in lipid, carbohydrates and cholesterol synthesis. These effects, which could contribute to promote hepatic steatosis, follow an inverted U shape non-monotonic dose-response curve and were observed below the reference dose in regulatory toxicology: the tolerable daily intake. These results strengthen the idea that BPA act as a metabolic disruptor, particularly at low doses. Nuclear receptors are targets through which metabolic disruptors may influence gene expression. Recent studies showed that the nuclear receptors CAR (Constitutive Receptor Androstane) and PXR (Pregnane X Receptor), initially identified as key receptors of the detoxification process, are also involved in the regulation of energy metabolism. We identified the gene coding for adiponutrin/PNPLA3 (Patatin-like phospholipase domain-containing) as a new target of these xenosensors. We have shown with transgenic animal models and with hepatocyte cell lines that the CAR and PXR receptors regulate the Pnpla3 gene expression. This protein has a central role in hepatic lipid metabolism through its dual transacylase and lipase activity. In human, a variant of the Pnpla3 (SNP I148M) gene has been identified as a new marker of hepatic steatosis and is associated with an increased risk of NAFLD. Since the xenosensors CAR and PXR are known to be activated by many drugs and environmental pollutants, our results highlight the risk of a development of hepatic steatosis after their activation. Taken together, these results highlight the risk of metabolic disruptions after exposure to various environmental contaminants such as endocrine disruptors and CAR activators. RÉSUMÉ De nombreuses études expérimentales, cliniques et épidémiologiques récentes montrent que l’exposition à des contaminants de notre environnement pourrait perturber les fonctions métaboliques et endocriniennes des organismes. Ceci contribuerait au développement de l'obésité et des pathologies métaboliques associées telles que la stéatose hépatique non alcoolique, caractérisée par une accumulation massive de triglycérides dans le foie, et qui est susceptible d’évoluer vers des pathologies plus sévères (inflammation, fibrose, cirrhose, carcinome hépatocellulaire), regroupées sous le terme de NAFLD (Non- Alcoholic Fatty Liver Diseases). Nos études réalisées chez le rongeur nous ont permis de mettre en évidence un impact sur le métabolisme hépatique suite à une exposition chronique au Bisphénol A (BPA), un contaminant oestrogéno-mimétique largement exploité dans l’industrie des emballages alimentaires plastiques. Il modifie l’expression des gènes impliqués dans la synthèse des lipides, des glucides et du cholestérol et favorise l’accumulation de triglycérides et d’esters de cholestérol au niveau hépatique. Ces effets, qui pourraient contribuer à l’émergence de la stéatose hépatique, ont été observés en deçà de la dose de référence en toxicologie réglementaire (la dose journalière admissible) et suivent une courbe dose-réponse non monotone en U inversé. Ces résultats renforcent l’idée que le BPA est un perturbateur métabolique, surtout lors d’expositions à faibles doses. Les récepteurs nucléaires représentent des cibles potentielles des perturbateurs métaboliques. Plusieurs études récentes montrent que les récepteurs nucléaires CAR (Constitutive Androstane Receptor) et PXR (Pregnane X Receptor), initialement identifiés comme des récepteurs clés du système de détoxification, sont également impliqués dans la régulation du métabolisme énergétique. Nos travaux ont permis d’identifier une nouvelle cible de ces xénosenseurs : le gène codant pour l’adiponutrine/PNPLA3 (Patatinlike phospholipase domain-containing). Nous avons montré, in vivo et sur des lignées d'hépatocytes en culture, que les récepteurs CAR et PXR régulent l’expression du gène Pnpla3. Cette protéine présente une activité à la fois transacylase et lipase qui lui confère un rôle central dans la régulation du métabolisme lipidique hépatique. Chez l’Homme, un variant du gène Pnpla3 (SNP I148M) a été identifié comme un nouveau marqueur de la stéatose hépatique et est associé à un risque accru de développement de NAFLD. Les xénosenseurs CAR et PXR étant activés par de nombreux médicaments et polluants environnementaux, nos résultats mettent en exergue le risque de développement de stéatoses hépatiques suite à leur activation. L’ensemble de ces résultats renforce l’idée d’un risque de développement de pathologies métaboliques suite à l’exposition à différents contaminants environnementaux, qu’il s’agisse de perturbateurs endocriniens de type métaboliques ou d’activateurs des xénosenseurs CAR et PXR.
    12/2012, Degree: PhD, Supervisor: Dr Laila MSELLI-LAKHAL ; Dr Thierry PINEAU

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