GATA binding protein 2 mediates leptin inhibition of PPARγ1 expression in hepatic stellate cells and contributes to hepatic stellate cell activation

Hepatic stellate cell (HSC) activation is a crucial step in the development of liver fibrosis. Peroxisome-proliferator activated receptor gamma (PPAR gamma) exerts a key role in the inhibition of HSC activation. Leptin reduces PPAR gamma expression in HSCs and plays a unique role in promoting liver fibrosis. The present studies aimed to investigate the mechanisms underlying leptin regulation of PPAR gamma 1 (a major subtype of PPAR gamma) in HSCs in vivo and in vitro. Results revealed a leptin response region in mouse PPAR gamma 1 promoter and indicated that the region included a GATA binding protein binding site around position -2323. GATA binding protein-2 (GATA-2) could bind to the site and inhibit PPAR gamma 1 promoter activity in HSCs. Leptin induced GATA-2 expression in HSCs in vitro and in vivo. GATA-2 mediated leptin inhibition of PPAR gamma 1 expression by its binding site in PPAR gamma 1 promoter in HSCs and GATA-2 promoted HSC activation. Leptin upregulated GATA-2 expression through beta-catenin and sonic hedgehog pathways in HSCs. Leptin-induced increase in GATA-2 was accompanied by the decrease in PPAR gamma expression in HSCs and by the increase in the activated HSC number and liver fibrosis in vivo. Our data might suggest a possible new explanation for the promotion effect of leptin on liver fibrogenesis. (C) 2014 Elsevier B.V. All rights reserved.