Sex-determining region Y-box 9 acts downstream of NADPH oxidase to influence the effect of leptin on PPARγl expression in hepatic stellate cells

Leptin, an adipocyte-derived hormone, promotes liver fibrogenesis and inhibits the expression of peroxisomeproliferator activated receptor gamma (PPAR gamma), a key transcription factor in inhibition of hepatic stellate cell (HSC) activation, in HSCs. This research aimed to further investigate the mechanisms underlying leptin regulation of PPAR gamma l in HSCs in vivo and in vitro. Results demonstrated that sex-determining region Y-box 9 (Sox9) could bind to a site around 2275 within leptin response region of PPAR gamma l promoter and inhibited PPAR gamma l expression. Sox9 upregulated the expressions of al (I)collagen and alpha-smooth muscle actin in HSCs. Leptin stimulated Sox9 expression and Sox9 binding to PPAR gamma l promoter. The signaling pathways of NADPH oxidase, beta-catenin, and delta like homologi (DLK1) mediated leptin upregulation of Sox9 expression. Moreover, there existed crosstalk between NADPH oxidase pathway and beta-catenin or DLK1 signaling pathway. Human liver specimens of cirrhosis were shown to be of a large number of the positive HSCs for p47phox (playing a central role in NADPH oxidase activity), 4hydroxynonenal (a lipid peroxidation product), Sox9, and alpha-smooth muscle actin whereas PPARy-positive HSCs were rarely detected. These results might deepen understanding of the molecular mechanisms for leptin inhibition of PPARyl expression in HSCs and for the liver fibrosis associated with leptin. (C) 2016 Elsevier B.V. All rights reserved.