Role of Leptin in Pathogenesis of NASH
Increasing lines of evidence indicate that obesity is an important risk factor for the exacerbation of alcoholic liver disease (ALD) and nonalcoholic steatohepatitis (NASH). Leptin, an obese gene product, is a cytokine-type hormone mainly produced from adipose tissue. Recently, it has been demonstrated that serum leptin levels are increased in patients with alcoholic cirrhosis. In this study, therefore, we investigated the role of leptin in hepatic fibrogenesis. Activated hepatic stellate cells (HSCs) produced leptin during hepatic fibrogenesis. Xenobiotic-induced hepatic fibrogenesis was almost completely abolished in ob/ob mice and Zucker (fa/fa) rats, which are inborn leptin- and leptin receptor (Ob-R)-deficient animals, respectively. Further, leptin increased transforming growth factor (TGF)-ß mRNA in isolated sinusoidal endothelial cells and Kupffer cells.Moreover, leptin augmented platelet-derived growth factor (PDGF)-dependent proliferation of HSCs. Taken together, these findings lead to the postulation that leptin acts as a profibrogenic cytokine in the sinusoidal microenvironment. In conclusion, leptin most likely plays a pivotal role in the progression of hepatic fibrosis in a variety of chronic liver diseases, including NASH.
Key wordsNASH Hepatic fibrogenesis Leptin Sinusoidal cells TGF-ß
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