Article

Human fatty liver disease: old questions and new insights.

Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA.
Science (Impact Factor: 31.48). 06/2011; 332(6037):1519-23. DOI: 10.1126/science.1204265
Source: PubMed

ABSTRACT Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem that affects one-third of adults and an increasing number of children in developed countries. The disease begins with the aberrant accumulation of triglyceride in the liver, which in some individuals elicits an inflammatory response that can progress to cirrhosis and liver cancer. Although NAFLD is strongly associated with obesity and insulin resistance, its pathogenesis remains poorly understood, and therapeutic options are limited. Here, we discuss recent mechanistic insights into NAFLD, focusing primarily on those that have emerged from human genetic and metabolic studies.

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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. 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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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