Jung, Yoon SeokLee, Ji-MinKim, Don-KyuLee, Yong-SooKim, Ki-SunKim, Yong-HoonKim, JinaLee, Myung-ShikLee, In-KyuKim, Seong HeonCho, Sung JinJeong, Wong-IlLee, Chul-HoHarris, Robert A.Choi, Hueng-Sik2017-06-072017-06-072016-07-25Jung, Y. S., Lee, J.-M., Kim, D.-K., Lee, Y.-S., Kim, K.-S., Kim, Y.-H., … Choi, H.-S. (2016). The Orphan Nuclear Receptor ERRγ Regulates Hepatic CB1 Receptor-Mediated Fibroblast Growth Factor 21 Gene Expression. PLoS ONE, 11(7), e0159425. http://doi.org/10.1371/journal.pone.0159425https://hdl.handle.net/1805/12904BACKGROUND: 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.en-USAttribution-NonCommercial-NoDerivs 3.0 United StatesFibroblast growth factor 21 (FGF21)HepatokineStressLiverGlucose -- MetabolismLipid -- MetabolismHepatic cannabinoid type 1 (CB1)Gene expressionArticle