Orphan nuclear receptor oestrogen-related receptor ? (ERR?) 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?-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?) is a novel transcriptional regulator of CYP7A1 expression. Activation of cannabinoid receptor type 1 (CB1 receptor) signalling induced ERR?-mediated transcription of the CYP7A1 gene. Overexpression of ERR? increased CYP7A1 expression in vitro and in vivo, whereas knockdown of ERR? attenuated CYP7A1 expression. Deletion analysis of the CYP7A1 gene promoter and a ChIP assay revealed an ERR?-binding site on the CYP7A1 gene promoter. Small heterodimer partner (SHP) inhibited the transcriptional activity of ERR? and thus regulated CYP7A1 expression. Overexpression of ERR? led to increased bile acid levels, whereas an inverse agonist of ERR?, 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? and bile acid metabolism.

SUBMITTER: Zhang Y 

PROVIDER: S-EPMC5333639 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature