Investigation of pathophysiology and therapeutic strategies for metabolic syndrome-related steatohepatitis

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Obesity and insulin resistance are the risk factors for progression hepatic fibrosis in various kinds of chronic liver diseases including alcoholic liver disease, non-alcoholic steatohepatitis (NASH) and chronic hepatitis C. It is hypothesized that a variety of adipokines plays a pivotal role in regulation of inflammation and fibrogenesis in fatty liver diseases. We and others have demonstrated that leptin attenuates hepatic inflammation caused by endotoxin. Further, leptin enhances profibrogenic responses in the liver through up-regulation of TGF-β in sinusoidal endothelial cells and Kupffer cells. Moreover, leptin directly enhances proliferation and matrix generation, and prevents apoptosis in isolated hepatic stellate cells (HSCs). Leptin prevents apoptosis of isolated HSCs caused by gliotoxin. This anti-apoptotic effect of leptin is abolished in cells isolated from Zucker (fa/fa) rats, which lack functional leptin receptors (ObR). In regular HSCs, leptin increases phosphorylation o … More f Akt, and LY295002 reverses the inhibitory effect of leptin on caspase 3 activation caused by gliotoxin. Taken tothether, it is postulated that the PI3K-Akt pathway downstream of ObR is important in anti-apoptotic effect of leptin in HSCs. To further evaluate the role of adipokines in NASH, we utilized KK-Ay mice, which demonstrate marked obesity and type-2 diabetes. These mice spontaneously developed mild steatohepatitis with regular diet ; however, they developed severe steatohepatitis with early progression of hepatic fibrosis when they were fed a methionine-, and choline-deficient (MCD) diet. Interestingly, KK-Ay mice not only showed low serum adiponectin levels before dietary treatments, but also lacked induction of adiponectin following dietary treatments, suggesting that adiponectin play a key role in prevention of hepatic inflammation and fibrogenesis in the setting of steatohepatitis. Collectively, these findings indicated that leptin and adiponectin are profoundly involved in the pathogenesis of steatohepatitis through actions on hepatic sinusoidal cells. Less