Orphan nuclear receptor oestrogen-related receptor gamma (ERR gamma) plays a key role in hepatic cannabinoid receptor type 1-mediated induction of CYP7A1 gene expression

Abstract

Bile acids are primarily synthesized from cholesterol in the liver and have important roles in dietary lipid absorption and cholesterol homoeostasis. Detailed roles of the orphan nuclear receptors regulating cholesterol 7 alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid synthesis, have not yet been fully elucidated. In the present study, we report that oestrogen-related receptor. (ERR gamma) is a novel transcriptional regulator of CYP7A1 expression. Activation of cannabinoid receptor type 1 (CB1 receptor) signalling induced ERR gamma-mediated transcription of the CYP7A1 gene. Overexpression of ERR gamma increased CYP7A1 expression in vitro and in vivo, whereas knockdown of ERR gamma attenuated CYP7A1 expression. Deletion analysis of the CYP7A1 gene promoter and a ChIP assay revealed an ERR gamma-binding site on the CYP7A1 gene promoter. Small heterodimer partner SHP) inhibited the transcriptional activity of ERR gamma and thus regulated CYP7A1 expression. Overexpression of ERR gamma led to increased bile acid levels, whereas an inverse agonist of ERR gamma, GSK5182, reduced CYP7A1 expression and bile acid synthesis. Finally, GSK5182 significantly reduced hepatic CB1 receptor-mediated induction of CYP7A1 expression and bile acid synthesis in alcohol-treated mice. These results provide the molecular mechanism linking ERR gamma and bile acid metabolism.