Estrogen-related receptor γ controls sterol regulatory element-binding protein-1c expression and alcoholic fatty liver

Don Kyu Kim, Yong Hoon Kim, Jae Ho Lee, Yoon Seok Jung, Jina Kim, Rilu Feng, Tae Il Jeon, In Kyu Lee, Sung Jin Cho, Seung Soon Im, Steven Dooley, Timothy F. Osborne, Chul Ho Lee, Hueng Sik Choi

Research output: Contribution to journalArticle

Abstract

Although SREBP-1c regulates key enzymes required for hepatic de novo lipogenesis, the mechanisms underlying transcriptional regulation of SREBP-1c in pathogenesis of alcoholic fatty liver is still incompletely understood. In this study, we investigated the role of ERRγ in alcohol-mediated hepatic lipogenesis and examined the possibility to ameliorate alcoholic fatty liver through its inverse agonist. Hepatic ERRγ and SREBP-1c expression was increased by alcohol-mediated activation of CB1 receptor signaling. Deletion and mutation analyses of the Srebp-1c gene promoter showed that ERRγ directly regulates Srebp-1c gene transcription via binding to an ERR-response element. Overexpression of ERRγ significantly induced SREBP-1c expression and fat accumulation in liver of mice, which were blocked in Srebp-1c-knockout hepatocytes. Conversely, liver-specific ablation of ERRγ gene expression attenuated alcohol-mediated induction of SREBP-1c expression. Finally, an ERRγ inverse agonist, GSK5182, significantly ameliorates fatty liver disease in chronically alcohol-fed mice through inhibition of SREBP-1c-mediated fat accumulation. ERRγ mediates alcohol-induced hepatic lipogenesis by upregulating SREBP-1c expression, which can be blunted by the inverse agonist for ERRγ, which may be an attractive therapeutic strategy for the treatment of alcoholic fatty liver disease in human.

Original languageEnglish (US)
Article number158521
JournalBiochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Volume1864
Issue number12
DOIs
StatePublished - Dec 2019

Keywords

  • Alcoholic fatty liver
  • CB receptor
  • ERRγ
  • Gene regulation
  • Hepatic lipogenesis
  • SREBP-1c

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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  • Cite this

    Kim, D. K., Kim, Y. H., Lee, J. H., Jung, Y. S., Kim, J., Feng, R., Jeon, T. I., Lee, I. K., Cho, S. J., Im, S. S., Dooley, S., Osborne, T. F., Lee, C. H., & Choi, H. S. (2019). Estrogen-related receptor γ controls sterol regulatory element-binding protein-1c expression and alcoholic fatty liver. Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, 1864(12), [158521]. https://doi.org/10.1016/j.bbalip.2019.158521