title: RORα switches transcriptional mode of ERRγ that results in transcriptional repression of CYP2E1 under ethanol-exposure.
abstract: Increased cytochrome P450 2E1 (CYP2E1) expression is the main cause of oxidative stress, which exacerbates alcoholic liver diseases (ALDs). Estrogen-related receptor gamma (ERRγ) induces CYP2E1 expression and contributes to enhancing alcohol-induced liver injury. Retinoic acid-related orphan receptor alpha (RORα) has antioxidative functions; however, potential cross-talk between ERRγ and RORα in the regulation of CYP2E1 has not been studied. We report that RORα suppressed ERRγ-mediated CYP2E1 expression. A physical interaction of RORα with ERRγ at the ERRγ-response element in the CYP2E1 promoter was critical in this suppression. At this site, coregulator recruitment of ERRγ was switched from coactivator p300 to the nuclear receptor corepressor 1 in the presence of RORα. Cross-talk between ERRγ and RORα was demonstrated in vivo, in that administration of JC1-40, a RORα activator, significantly decreased both CYP2E1 expression and the signs of liver injury in ethanol-fed mice, and this was accompanied by coregulator switching. Thus, this non-classical RORα pathway switched the transcriptional mode of ERRγ, leading to repression of alcohol-induced CYP2E1 expression, and this finding may provide a new therapeutic strategy against ALDs.
authors.affiliation: From the College of Pharmacy and Bio-MAX institute, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Yong-Hyun
authors.initials: YH
authors.lastname: Han
authors.affiliation: National Creative Research Initiatives Center for Nuclear Receptor Signals, Hormone Research Center, School of Biological Sciences and Technology, Gwangju, Chonnam 500-757, Korea.
authors.forename: Don-Kyu
authors.initials: DK
authors.lastname: Kim
authors.affiliation: From the College of Pharmacy and Bio-MAX institute, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Tae-Young
authors.initials: TY
authors.lastname: Na
authors.affiliation: From the College of Pharmacy and Bio-MAX institute, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Na-Lee
authors.initials: NL
authors.lastname: Ka
authors.affiliation: National Creative Research Initiatives Center for Nuclear Receptor Signals, Hormone Research Center, School of Biological Sciences and Technology, Gwangju, Chonnam 500-757, Korea hsc@chonnam.ac.kr.
authors.forename: Hueng-Sik
authors.initials: HS
authors.lastname: Choi
authors.affiliation: From the College of Pharmacy and Bio-MAX institute, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Korea molee@snu.ac.kr.
authors.forename: Mi-Ock
authors.initials: MO
authors.lastname: Lee
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics*; D000431:Ethanol / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000502:physiology*; D011960:Receptors, Estrogen / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology*
chemical_list: C490916:Esrrg protein, mouse; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D011960:Receptors, Estrogen; C539739:Rora protein, mouse; D000431:Ethanol; D019392:Cytochrome P-450 CYP2E1