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The Orphan Nuclear Receptor ERRγ 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 A. Harris  ;  Hueng-Sik Choi 
 PLOS ONE, Vol.11(7) : e0159425, 2016 
Journal Title
Issue Date
Animals ; Cell Line ; Fibroblast Growth Factors/genetics* ; Gene Expression Regulation*/drug effects ; Gene Knockdown Techniques ; Hepatocytes/metabolism* ; Humans ; Male ; Mice ; Mice, Knockout ; Orphan Nuclear Rceptors/genetics ; Orphan Nuclear Receptors/metabolism* ; Promoter Regions, Genetic ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Receptor, Cannabinoid, CB1/agonists ; Receptor, Cannabinoid, CB1/metabolism* ; Receptors, Estrogen/genetics ; Receptors, Estrogen/metabolism* ; Tamoxifen/analogs & derivatives ; Tamoxifen/pharmacology
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.
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1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Lee, Myung Shik(이명식) ORCID logo https://orcid.org/0000-0003-3292-1720
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