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: Nonalcoholic fatty liver disease (NAFLD) is a distinct pathologic condition characterized by a disease spectrum ranging from simple steatosis to steato-hepatitis, cirrhosis and hepatocellular carcinoma. Prevalence of NAFLD varies in different ethnic groups, ranging from 12% in Chinese to 45% in Hispanics. Among Indian populations, the diversity in prevalence is high, ranging from 9% in rural populations to 32% in urban populations, with geographic differences as well. Here, we wished to find out if this difference is reflected in their genetic makeup. To date, several candidate genes and a few genomewide association studies (GWAS) have been carried out, and many associations between single nucleotide polymorphisms (SNPs) and NAFLD have been observed. In this study, the risk allele frequencies (RAFs) of NAFLD-associated SNPs in 20 Indian ethnic populations (376 individuals) were analysed. We used two different measures for calculating genetic risk scores and compared their performance. The correlation of additive risk scores of NAFLD for three Hapmap populations with their weighted mean prevalence was found to be high (R 2 = 0.93). Later we used this method to compare NAFLD risk among ethnic Indian populations. Based on our observation, the Indian caste populations have high risk scores compared to Caucasians, who are often used as surrogate and similar to Indian caste population in disease gene association studies, and is significantly higher than the Indian tribal populations.. 2015 Comparative analyses of genetic risk prediction methods reveal extreme diversity of genetic predisposition to nonalcoholic fatty liver disease (NAFLD) among ethnic populations of India. J. Genet. 94, xx–xx]
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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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