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


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.



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.


  1. 1.
    Zhang Y, et al. (1994) Positional cloning of the mouse obese gene and its human homologue. Nature. 372:425–32.CrossRefGoogle Scholar
  2. 2.
    William WN Jr, Ceddia RB, Curi R. (2002) Leptin controls the fate of fatty acids in isolated rat white adipocytes. J. Endocrinol. 175:735–44.CrossRefGoogle Scholar
  3. 3.
    Zhou YT, Wang ZW, Higa M, Newgard CB, Unger RH. (1999) Reversing adipocyte differentiation: implications for treatment of obesity. Proc. Natl. Acad. Sci. U. S. A. 96:2391–5.CrossRefGoogle Scholar
  4. 4.
    García-Suárez C, et al. (2004) Plasma leptin levels in patients with primary biliary cirrhosis and their relationship with degree of fibrosis. Gastroenterol. Hepatol. 27:47–50.CrossRefGoogle Scholar
  5. 5.
    Henriksen JH, Holst JJ, Møller S, Brinch K, Bendtsen F. (1999) Increased circulating leptin in alcoholic cirrhosis: relation to release and disposal. Hepatology. 29:1818–24.CrossRefGoogle Scholar
  6. 6.
    Aleffi S, et al. (2005) Upregulation of proinflammatory and proangiogenic cytokines by leptin in human hepatic stellate cells. Hepatology. 42:1339–48.CrossRefGoogle Scholar
  7. 7.
    Cao Q, Mak KM, Lieber CS. (2006) Leptin enhances alpha1(I) collagen gene expression in LX-2 human hepatic stellate cells through JAK-mediated H2O2-dependent MAPK pathways. J. Cell. Biochem. 97:188–97.CrossRefGoogle Scholar
  8. 8.
    Saxena NK, Ikeda K, Rockey DC, Friedman SL, Anania FA. (2002) Leptin in hepatic fibrosis: evidence for increased collagen production in stellate cells and lean littermates of ob/ob mice. Hepatology. 35:762–71.CrossRefGoogle Scholar
  9. 9.
    Tang Y, Chen A. (2010) Curcumin protects hepatic stellate cells against leptin-induced activation in vitro by accumulating intracellular lipids. Endocrinology. 151:4168–77.CrossRefGoogle Scholar
  10. 10.
    Zhou Y, et al. (2010) Leptin inhibits PPARgamma gene expression in hepatic stellate cells in the mouse model of liver damage. Mol. Cell. Endocrinol. 323:193–200.CrossRefGoogle Scholar
  11. 11.
    Tsukamoto H. (2005) Adipogenic phenotype of hepatic stellate cells. Alcohol Clin. Exp. Res. 29:132S–3S.CrossRefGoogle Scholar
  12. 12.
    Rangwala SM, Lazar MA. (2000) Transcriptional control of adipogenesis. Annu. Rev. Nutr. 20:535–59.CrossRefGoogle Scholar
  13. 13.
    Shimomura I, Shimano H, Horton JD, Goldstein JL, Brown MS. (1997) Differential expression of exons 1a and 1c in mRNAs for sterol regulatory element binding protein-1 in human and mouse organs and cultured cells. J. Clin. Invest. 99:838–45.CrossRefGoogle Scholar
  14. 14.
    She H, Xiong S, Hazra S, Tsukamoto H. (2005) Adipogenic transcriptional regulation of hepatic stellate cells. J. Biol. Chem. 280:4959–67.CrossRefGoogle Scholar
  15. 15.
    Potter JJ, Womack L, Mezey E, Anania FA. (1998) Transdifferentiation of rat hepatic stellate cells results in leptin expression. Biochem. Biophys. Res. Commun. 244:178–82.CrossRefGoogle Scholar
  16. 16.
    Honda H, et al. (2002) Leptin is required for fibrogenic responses induced by thioacetamide in the murine liver. Hepatology. 36:12–21.CrossRefGoogle Scholar
  17. 17.
    Cassiman D, et al. (1999) Synaptophysin: a novel marker for human and rat hepatic stellate cells. Am. J. Pathol. 155:1831–9.CrossRefGoogle Scholar
  18. 18.
    Kammoun HL, et al. (2009) GRP78 expression inhibits insulin and ER stress-induced SREBP-1c activation and reduces hepatic steatosis in mice. J. Clin. Invest. 119:1201–15.CrossRefGoogle Scholar
  19. 19.
    Zhou Y, Jia X, Wang G, Wang X, Liu J. (2009) PI-3 K/AKT and ERK signaling pathways mediate leptin-induced inhibition of PPARgamma gene expression in primary rat hepatic stellate cells. Mol. Cell. Biochem. 325:131–9.CrossRefGoogle Scholar
  20. 20.
    Schmittgen TD, et al. (2000) Quantitative reverse transcription-polymerase chain reaction to study mRNA decay: comparison of endpoint and realtime methods. Anal. Biochem. 285:194–204.CrossRefGoogle Scholar
  21. 21.
    Cagen LM, et al. (2005) Insulin activates the rat sterol-regulatory-element-binding protein 1c (SREBP-1c) promoter through the combinatorial actions of SREBP, LXR, Sp-1 and NF-Y cis-acting elements. Biochem. J. 385:207–16.CrossRefGoogle Scholar
  22. 22.
    Lee YS, et al. (2003) Twist2, a novel ADD1/SREBP1c interacting protein, represses the transcriptional activity of ADD1/SREBP1c. Nucleic Acids Res. 31:7165–74.CrossRefGoogle Scholar
  23. 23.
    Mastrogiannaki M, et al. (2009) HIF-2alpha, but not HIF-1alpha, promotes iron absorption in mice. J. Clin. Invest. 119:1159–66.CrossRefGoogle Scholar
  24. 24.
    Lin J, Chen A. (2011) Curcumin diminishes the impacts of hyperglycemia on the activation of hepatic stellate cells by suppressing membrane translocation and gene expression of glucose transporter-2. Mol. Cell. Endocrinol. 333:160–7.CrossRefGoogle Scholar
  25. 25.
    Schnabl B, et al. (2001) TAK1/JNK and p38 have opposite effects on rat hepatic stellate cells. Hepatology. 34:953–63.CrossRefGoogle Scholar
  26. 26.
    Lu TT, Repa JJ, Mangelsdorf DJ. (2001) Orphan nuclear receptors as eLiXiRs and FiXeRs of sterol metabolism. J. Biol. Chem. 276:37735–8.CrossRefGoogle Scholar
  27. 27.
    Horton JD, Goldstein JL, Brown MS. (2002) SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J. Clin. Invest. 109:1125–31.CrossRefGoogle Scholar
  28. 28.
    Nogalska A, Sucajtys-Szulc E, Swierczynski J. (2005) Leptin decreases lipogenic enzyme gene expression through modification of SREBP-1c gene expression in white adipose tissue of aging rats. Metabolism. 54:1041–7.CrossRefGoogle Scholar
  29. 29.
    Rippe RA, Almounajed G, Brenner DA. (1995) Sp1 binding activity increases in activated Ito cells. Hepatology. 22:241–51.PubMedGoogle Scholar
  30. 30.
    Chen G, Liang G, Ou J, Goldstein JL, Brown MS. (2004) Central role for liver X receptor in insulin-mediated activation of Srebp-1c transcription and stimulation of fatty acid synthesis in liver. Proc. Natl. Acad. Sci. U. S. A. 101:11245–50.CrossRefGoogle Scholar
  31. 31.
    Repa JJ, et al. (2000) Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRalpha and LXRbeta. Genes. Dev. 14:2819–30.CrossRefGoogle Scholar
  32. 32.
    Ratziu V, et al. (2000) Liver fibrosis in overweight patients. Gastroenterology. 118:1117–23.CrossRefGoogle Scholar
  33. 33.
    McCullough AJ, Falck-Ytter Y. (1999) Body composition and hepatic steatosis as precursors for fibrotic liver disease. Hepatology. 29:1328–9.CrossRefGoogle Scholar
  34. 34.
    Faggioni R, Feingold KR, Grunfeld C. (2001) Leptin regulation of the immune response and the immunodeficiency of malnutrition. FASEB J. 15:2565–71.CrossRefGoogle Scholar
  35. 35.
    Van der Poorten D, George J. (2008) Disease-specific mechanisms of fibrosis: hepatitis C virus and nonalcoholic steatohepatitis. Clin. Liver Dis. 12:805–824, ix.CrossRefGoogle Scholar
  36. 36.
    Uygun A, et al. (2000) Serum leptin levels in patients with nonalcoholic steatohepatitis. Am. J. Gastroenterol. 95:3584–9.CrossRefGoogle Scholar
  37. 37.
    Nakamura T, et al. (2001) Clinical implication of serial leptin measurement in subjects with type 2 diabetes mellitus. Endocr. J. 48:87–94.CrossRefGoogle Scholar
  38. 38.
    McCullough AJ, Bugianesi E, Marchesini G, Kalhan SC. (1998) Gender-dependent alterations in serum leptin levels in alcoholic cirrhosis. Gastroenterology. 115:947–53.CrossRefGoogle Scholar
  39. 39.
    Polyzos SA, Kountouras J, Zavos C, Deretzi G. (2011) The potential adverse role of leptin resistance in nonalcoholic fatty liver disease: a hypothesis based on critical review of the literature. J. Clin. Gastroenterol. 45:50–4.CrossRefGoogle Scholar

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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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