title: Liver fibrogenesis and metabolic factors.
abstract: Mechanisms of liver fibrosis are complex and varied. Among them, metabolic factors are particularly important in the development of fibrosis associated with nonalcoholic steatohepatitis (NASH). These factors are some of the "multiple parallel hits" responsible for liver damage during NASH. Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. Major profibrogenic protagonists, such as hepatic stellate cells and Kupffer cells, are activated by insulin resistance, apoptosis and local inflammation. Relations between steatosis, insulin resistance and fibrosis are complex. Initially, simple steatosis may be a way to store deleterious free fatty acid in neutral triglycerides. If the lipid storage threshold is exceeded, steatosis may become associated with lipotoxicity. Similarly, interindividual variations of adipose tissue expandability might explain various phenotypes, ranging from "metabolically obese patients with normal weight" to "metabolically normal morbidly obese patients". The metabolic abnormalities in subcutaneous and visceral adipose tissue are insulin resistance and low-grade inflammation, which are associated with increased release of free fatty acid flux and changes in adipocytokines production such as leptin, adiponectin and interleukin 6. The nuclear transcription factor peroxisome proliferator-activated receptor gamma (PPARγ) and the endocannabinoid system might have important roles in liver fibrogenesis and are potential therapeutic targets. Finally, with the development of new molecular tools, gut microbiota has been recently identified for its pleiotropic functions, including metabolism regulation. Better knowledge of these mechanisms should lead to new strategies for the treatment of metabolic factors that play a key role in liver injuries.
authors: Institut National de la Santé et de la Recherche Médicale, U895, Team 8, Hepatic Complications in Obesity, Nice F-06204, Cedex 3, France. anty.r@chu-nice.fr
authors: Rodolphe
authors: R
authors: Anty
authors: Maud
authors: M
authors: Lemoine
mesh_terms: D054392:Adipokines / Q000378:metabolism; D052242:Adiponectin / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D015992:Body Mass Index; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D005234:Fatty Liver / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D007728:Kupffer Cells / Q000378:metabolism; D020738:Leptin / Q000378:metabolism; D008103:Liver Cirrhosis / Q000378:metabolism*; D024821:Metabolic Syndrome / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease; D047495:PPAR gamma / Q000378:metabolism*; D012307:Risk Factors
chemical_list: D054392:Adipokines; D052242:Adiponectin; D015415:Biomarkers; D063385:Cannabinoid Receptor Modulators; D015850:Interleukin-6; D020738:Leptin; D047495:PPAR gamma