The Orphan Nuclear Receptor ERR? 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) ? 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?, but not ERR? and ERR?, induced FGF21 gene promoter activity. In addition, deletion and mutation analysis of the FGF21 promoter identified a putative ERR?-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? plays a key role in hepatic CB1 receptor-mediated induction of FGF21 gene expression and secretion.

SUBMITTER: Jung YS 

PROVIDER: S-EPMC4959684 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature