Orphan nuclear receptor oestrogen-related receptor γ (ERRγ) plays a key role in hepatic cannabinoid receptor type 1-mediated induction of CYP7A1 gene expression.
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 7α-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 γ (ERRγ) is a novel transcriptional regulator of CYP7A1 expression. Activation of cannabinoid receptor type 1 (CB1 receptor) signalling induced ERRγ-mediated transcription of the CYP7A1 gene. Overexpression of ERRγ increased CYP7A1 expression in vitro and in vivo, whereas knockdown of ERRγ attenuated CYP7A1 expression. Deletion analysis of the CYP7A1 gene promoter and a ChIP assay revealed an ERRγ-binding site on the CYP7A1 gene promoter. Small heterodimer partner (SHP) inhibited the transcriptional activity of ERRγ and thus regulated CYP7A1 expression. Overexpression of ERRγ led to increased bile acid levels, whereas an inverse agonist of ERRγ, 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 ERRγ and bile acid metabolism.
National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea.
Yaochen
Y
Zhang
National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea.
Don-Kyu
DK
Kim
National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea.
Ji-Min
JM
Lee
Chemical Biology Laboratory, School of Chemistry, Seoul National University, Seoul 151-742, Republic of Korea.
Seung Bum
SB
Park
Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon 305-338, Republic of Korea.
Won-Il
WI
Jeong
New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 701-310, Republic of Korea.
Seong Heon
SH
Kim
Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu 700-721, Republic of Korea.
In-Kyu
IK
Lee
Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Republic of Korea.
Chul-Ho
CH
Lee
Department of Integrative Medical Sciences, Northeastern Ohio University's Colleges of Medicine and Pharmacy, Rootstown, Ohio 44272, U.S.A.
John Y L
JY
Chiang
National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea hsc@chonnam.ac.kr.
Hueng-Sik
HS
Choi
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D002478:Cells, Cultured; D002790:Cholesterol 7-alpha-Hydroxylase / Q000096:biosynthesis* / Q000235:genetics; D054314:Drug Inverse Agonism; D000431:Ethanol / Q000494:pharmacology; D015870:Gene Expression; D005989:Glycerides / Q000494:pharmacology; D057809:HEK293 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
D001647:Bile Acids and Salts; C490916:Esrrg protein, mouse; D005989:Glycerides; D043884:Receptor, Cannabinoid, CB1; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; C099713:nuclear receptor subfamily 0, group B, member 2; C424442:noladin ether; D000431:Ethanol; D002790:Cholesterol 7-alpha-Hydroxylase; C502772:Cyp7a1 protein, mouse
GSK5182; bile acid; cannabinoid receptors; cholesterol 7α-hydroxylase (CYP7A1); oestrogen-related receptor γ (ERRγ); orphan nuclear receptor; small heterodimer partner (SHP)