The Orphan Nuclear Receptor ERR gamma Regulates Hepatic CB1 Receptor-Mediated Fibroblast Growth Factor 21 Gene Expression

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) gamma increased FGF21 gene expression and secretion both in hepatocytes and mice, whereas knockdown of ERR. decreased ACEA-mediated FGF21 gene expression and secretion. Moreover, ERR gamma, but not ERR alpha and ERR beta, induced FGF21 gene promoter activity. In addition, deletion and mutation analysis of the FGF21 promoter identified a putative ERR gamma-binding motif (AGGTGC, a near-consensus response element). A chromatin immunoprecipitation assay revealed direct binding of ERR. to the FGF21 gene promoter. Finally, GSK5182, an ERR. inverse agonist, significantly inhibited hepatic CB1 receptor-mediated FGF21 gene expression and secretion. Conclusion Based on our data, we conclude that ERR gamma plays a key role in hepatic CB1 receptor-mediated induction of FGF21 gene expression and secretion