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Molecular Medicine

, Volume 18, Issue 1, pp 10–18 | Cite as

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

  • Kunfeng Yan
  • Xiong Deng
  • Xuguang Zhai
  • Mingming Zhou
  • Xin Jia
  • Lin Luo
  • Minghui Niu
  • Huixia Zhu
  • Hui Qiang
  • Yajun Zhou
Research Article

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.

Notes

Acknowledgments

We are grateful to the scientists for their important help. Plasmid pSREBP1c-Luc and plasmid pmutLXRE-Luc were the gifts from Xiong Deng (University of Tennessee Health Sciences Center, Memphis, TN, USA). Plasmid pdnP38, plasmid pwtP38, plasmid pSP1, plasmid pSp1-Luc, plasmid pNFY-Luc, plasmid pLXRE-Luc, plasmid pLXRa and plasmid ptwist2 were provided by Jiahuai Han (Xiamen University, Xiamen, China), Zhengui Xia (University of Washington, Seattle, WA, USA), Guntrum Suske (Philipps-University, Marburg, Germany), Toshiyuki Sakai (Kyoto Prefectural University of Medicine, Kyoto, Japan), Bart J.L. Eggen (University of Groningen, Haren, the Netherlands), David J. Mangelsdorf (University of Texas Southwestern Medical Center, Dallas, TX, USA), Hitoshi Shimano (University of Tsukuba, Ibaraki, Japan) and Jae Bum Kim (Seoul National University, Seoul, Korea), respectively.

This work was supported by a grant from the National Science Foundation of China (30971117 to Y Zhou) and the project funded by the Priority Academic Program Development of Jiangsu Higher Education Institution.

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Authors and Affiliations

  • Kunfeng Yan
    • 1
  • Xiong Deng
    • 2
  • Xuguang Zhai
    • 1
  • Mingming Zhou
    • 1
  • Xin Jia
    • 1
  • Lin Luo
    • 1
  • Minghui Niu
    • 1
  • Huixia Zhu
    • 1
  • Hui Qiang
    • 3
  • Yajun Zhou
    • 1
  1. 1.Department of Biochemistry and Molecular Biology, Medical CollegeNantong UniversityJiangsuChina
  2. 2.Department of PharmacologyUniversity of Tennessee Health Sciences CenterMemphisUSA
  3. 3.Affiliated Hospital of Nantong UniversityJiangsuChina

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