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

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

Zhang Yaochen; Kim Don-Kyu; Lee Ji-Min; Park Seung Bum; Jeong Won-Il; Kim Seong Heon; Lee In-Kyu; Lee Chul-Ho; Chiang John Y L; Choi Hueng-Sik

The Biochemical journal

2015

2015-09

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 7alpha-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 gamma (ERRgamma) is a novel transcriptional regulator of CYP7A1 expression. Activation of cannabinoid receptor type 1 (CB1 receptor) signalling induced ERRgamma-mediated transcription of the CYP7A1 gene. Overexpression of ERRgamma increased CYP7A1 expression in vitro and in vivo, whereas knockdown of ERRgamma attenuated CYP7A1 expression. Deletion analysis of the CYP7A1 gene promoter and a ChIP assay revealed an ERRgamma-binding site on the CYP7A1 gene promoter. Small heterodimer partner (SHP) inhibited the transcriptional activity of ERRgamma and thus regulated CYP7A1 expression. Overexpression of ERRgamma led to increased bile acid levels, whereas an inverse agonist of ERRgamma, 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 ERRgamma and bile acid metabolism.

Animals; bile acid; Bile Acids and Salts/metabolism; Cannabinoid; cannabinoid receptors; CB1/agonists/genetics/*metabolism; Cells; Cholesterol 7-alpha-Hydroxylase/*biosynthesis/genetics; cholesterol 7alpha-hydroxylase (CYP7A1); Cultured; Cytoplasmic and Nuclear/metabolism; Drug Inverse Agonism; Estrogen/genetics/*metabolism; Ethanol/pharmacology; Gene Expression; Genetic; Glycerides/pharmacology; GSK5182; HEK293 Cells; Hepatocytes/metabolism; Humans; Inbred C57BL; Knockout; Liver/*metabolism; Mice; oestrogen-related receptor gamma (ERRgamma); orphan nuclear receptor; Promoter Regions; Rats; Receptor; Receptors; small heterodimer partner (SHP); Sprague-Dawley; Transcription

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