title: p38 mitogen-activated protein kinase and liver X receptor-α mediate the leptin effect on sterol regulatory element binding protein-1c expression in hepatic stellate cells.
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.
authors: Department of Biochemistry and Molecular Biology, Medical College, Nantong University, Jiangsu, China.
authors: Kunfeng
authors: K
authors: Yan
authors: Xiong
authors: X
authors: Deng
authors: Xuguang
authors: X
authors: Zhai
authors: Mingming
authors: M
authors: Zhou
authors: Xin
authors: X
authors: Jia
authors: Lin
authors: L
authors: Luo
authors: Minghui
authors: M
authors: Niu
authors: Huixia
authors: H
authors: Zhu
authors: Hui
authors: H
authors: Qiang
authors: Yajun
authors: Y
authors: Zhou
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism*; D020738:Leptin / Q000494:pharmacology*; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D016708:Synaptophysin / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D020738:Leptin; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; C000605215:Nr1h3 protein, rat; D057093:Orphan Nuclear Receptors; D051780:Sterol Regulatory Element Binding Protein 1; D016708:Synaptophysin; D048051:p38 Mitogen-Activated Protein Kinases