Stat3 pathway correlates with the roles of leptin in mouse liver fibrosis and sterol regulatory element binding protein-1c expression of rat hepatic stellate cells

Abstract

Leptin, the adipocyte-derived hormone, plays an unique role in promoting liver fibrosis. Hepatic stellate cell (HSC) activation is the key step in liver fibrogenesis and sterol regulatory element binding protein-1c (SREBP-1c, a pivotal transcription factor for adipocyte differentiation) exerts a critical function in inhibition of HSC activation. Stat3 pathway is the main pathway induced by leptin and its role in liver fibrogenesis is controversial. Our previous results demonstrated the inhibitory effect of leptin on SREBP-1c expression in HSCs. The present study aimed to explore the role of Stat3 pathway in leptin-induced liver fibrogenesis in mouse model, focusing on examining the effect of leptin-induced Stat3 pathway on SREBP-1c expression in HSCs in vitro and in vivo. Results suggested that Stat3 pathway mediated the promotional role of leptin in liver fibrosis in mouse and was involved in leptin inhibition of SREBP-1c expression in HSCs. Leptin-induced Stat3 activation was, at least partially, ERK pathway-dependent in cultured HSCs and was correlated positively with β-catenin activity and negatively with liver X receptor α expression and activity which influenced SREBP-1c expression in HSCs. The decrease in SREBP-1c expression by leptin-induced Stat3 pathway led to the increase in the marker for HSC activation and in α1(I) collagen expression in HSCs. In summary, the effect of leptin-induced Stat3 pathway on SREBP-1c expression in HSCs might contribute to the role of leptin in liver fibrosis in mouse, thus advancing understanding of the mechanisms of liver fibrogenesis associated with leptin.