The orphan nuclear receptor erraγ regulates hepatic cb1 receptor-mediated fibroblast growth factor 21 gene expression

Yoon Seok Jung, Ji Min Lee, Don Kyu Kim, Yong Soo Lee, Ki Sun Kim, Yong Hoon Kim, Jina Kim, Myung Shik Lee, In Kyu Lee, Seong Heon Kim, Sung Jin Cho, Won Il Jeong, Chul Ho Lee, Robert Harris, Hueng Sik Choi

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7 Scopus citations

Abstract

Background Fibroblast growth factor 21 (FGF21), a stress inducible hepatokine, is synthesized in the liver and plays important roles in glucose and lipid metabolism. However, the mechanism of hepatic cannabinoid type 1 (CB1) receptor-mediated induction of FGF21 gene expression is largely unknown. Results Activation of the hepatic CB1 receptor by arachidonyl-2'-chloroethylamide (ACEA), a CB1 receptor selective agonist, significantly increased FGF21 gene expression. Overexpression of estrogen-related receptor (ERR) γ increased FGF21 gene expression and secretion both in hepatocytes and mice, whereas knockdown of ERRγ decreased ACEA-mediated FGF21 gene expression and secretion. Moreover, ERRγ , but not ERRα and ERRβ, induced FGF21 gene promoter activity. In addition, deletion and mutation analysis of the FGF21 promoter identified a putative ERRγ -binding motif (AGGTGC, a near-consensus response element). A chromatin immunoprecipitation assay revealed direct binding of ERRγ to the FGF21 gene promoter. Finally, GSK5182, an ERRγ inverse agonist, significantly inhibited hepatic CB1 receptor-mediated FGF21 gene expression and secretion. Conclusion Based on our data, we conclude that ERRγ plays a key role in hepatic CB1 receptor-mediated induction of FGF21 gene expression and secretion.

Original languageEnglish (US)
Article numbere0159425
JournalPLoS One
Volume11
Issue number7
DOIs
StatePublished - Jul 1 2016

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ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Jung, Y. S., Lee, J. M., Kim, D. K., Lee, Y. S., Kim, K. S., Kim, Y. H., Kim, J., Lee, M. S., Lee, I. K., Kim, S. H., Cho, S. J., Jeong, W. I., Lee, C. H., Harris, R., & Choi, H. S. (2016). The orphan nuclear receptor erraγ regulates hepatic cb1 receptor-mediated fibroblast growth factor 21 gene expression. PLoS One, 11(7), [e0159425]. https://doi.org/10.1371/journal.pone.0159425