Role of leptin in progression of alcoholic and non-alcoholic steatohepatitis

Abstract

Accumulating lines of evidence suggest that alcoholic liver disease (ALD) and non-alcoholic steatohepatitis (NASH) share a common patho-physiological basis in terms of inflammation and fibrogenesis. It is well known that NASH is accompanied by metabolic syndrome comprising obesity, type-2 diabetes and hypertension. In addition, recent epidemiological studies have revealed that obesity is an important risk factor in progression of ALD. It is hypothesized that adipocytokines, insulin resistance and autonomic nervous regulation play causative roles in the disease progression of ALD and NASH. In this study, therefore, we focused on the role of leptin in inflammation and fibrogenesis in the liver. Activated hepatic stellate cells (HSCs) produce leptin during hepatic fibrogenesis. Xenobiotic-induced liver fibrosis was extremely diminished in ob/ob mice and Zucker (fa/fa) rats, inborn leptin-and leptin receptor (Ob-R) -deficient animals, respectively. Further, leptin increased TGF-β mRNA in isolated sinusoidal endothelial cells and Kupffer cells. Moreover, leptin augmented PDGF-dependent proliferation of HSCs. Taken together, it is postulated that leptin acts as a profibrogenic cytokine in sinusoidal microenvironment. In conclusion, leptin most likely plays a pivotal role in the progression of hepatic fibrosis in ALD and NASH.