PI-3 K/AKT and ERK signaling pathways mediate leptin-induced inhibition of PPARgamma gene expression in primary rat hepatic stellate cells.

Compelling evidence indicates the pro-fibrogenic action of leptin in liver. Peroxisome proliferator-activated receptor-gamma (PPARgamma) can reverse hepatic stellate cell (HSC) activation and maintain HSC quiescence. HSC activation, a key step in the development of liver fibrosis, is coupled with the up-expression of leptin and the dramatic down-expression of PPARgamma. The present study is aimed to assess the effect of leptin on PPARgamma gene expression in primary cultured rat HSCs and investigate the related mechanisms by using Western blotting analysis, real-time PCR, transient transfection approach, and cell growth analysis. The results suggest that leptin negatively regulates PPARgamma gene expression at mRNA level, protein level and PPARgamma gene promoter activity level in HSCs. The inhibitory effect of leptin on PPARgamma gene expression contributes to cell growth of activated HSCs in vitro. Phosphatidylinositol 3-kinase/AKT (PI-3 K/AKT) and extracellular signal-regulated kinase (ERK) signaling pathways mediate the leptin-induced inhibition of PPARgamma gene expression. In summary, these findings suggest that leptin down-regulates PPARgamma gene expression through activation of PI-3 K/AKT or ERK signaling pathway in primary cultured rat HSCs. Our results might provide novel insights into the mechanisms for the pro-fibrogenic action of leptin in liver.