Abstract
Leptin, a key hormone in regulating energy homeostasis, is mainly produced by adipocytes. Cogent evidence indicates a unique role of leptin in the promotion of liver fibrosis. Hepatic stellate cell (HSC) activation is a pivotal step in the process of liver fibrosis. Sterol regulatory element binding protein (SREBP)-1c, a critical transcription factor for lipid synthesis and adipocyte differentiation, functions as a key transcription factor in inhibition of HSC activation. SREBP-1c is highly expressed in quiescent HSCs and downregulated upon HSC activation. The aim of this study is to examine the effect of leptin on SREBP-1c gene expression in HSCs in vitro and in vivo and elucidate the underlying mechanisms. The results of the present study demonstrated that leptin strongly inhibited SREBP-1c expression in HSCs in vivo and in vitro. p38 MAPK was involved in leptin regulation of SREBP-1c expression in cultured HSCs. Leptin-induced activation of p38 MAPK led to the decreases in liver X receptor (LXR)-α protein level, activity and its binding to the SREBP-1c promoter, which caused the downregulation of SREBP-1c expression. Moreover, leptin inhibition of SREBP-1c expression via p38 MAPK increased the expression of alpha1(I) collagen in HSCs. Our results might provide new insights into the mechanisms of the unique role of leptin in the development of liver fibrosis and might have potential implications for clarifying the molecular mechanisms underlying liver fibrosis in diseases in which circulating leptin levels are elevated such as nonalcoholic steatohepatitis, type 2 diabetes mellitus and alcoholic cirrhosis.
Highlights
Leptin, the product of the obese gene, is mainly produced by adipocyte [1]
To elucidate whether leptin has an effect on Sterol regulatory element binding protein (SREBP)-1c promoter activity, Hepatic stellate cell (HSC) were transfected with a SREBP-1c promoter luciferase reporter plasmid pSREBP1cLuc and incubated with or without leptin
The plasmid pmutLXRE-Luc or pSREBP1c-Luc was transfected into HSCs, and the cells were stimulated with or without leptin for 24 h
Summary
The product of the obese gene, is mainly produced by adipocyte [1]. It inhibits free fatty acid uptake and de novo fatty acid synthesis, stimulates free fatty acid mobilization and oxidation and reverses adipocyte differentiation [2,3]. Hepatic stellate cell (HSC) activation is a pivotal step in the development of liver fibrosis. Stimulate HSC activation and fibrogenesis [8,9,10]. Quiescent HSCs, once called fat-storing cells, are much like adipocytes. It is proposed that HSC transdifferentiation from quiescent to myofibroblastic cells is analogous to adipocyte to preadipocyte (fibroblast) transdifferentiation [11]
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