title: Estrogen-related receptor γ controls hepatic CB1 receptor-mediated CYP2E1 expression and oxidative liver injury by alcohol.
abstract: BACKGROUND
  The hepatic endocannabinoid system and cytochrome P450 2E1 (CYP2E1), a key enzyme causing alcohol-induced reactive oxygen species (ROS) generation, are major contributors to the pathogenesis of alcoholic liver disease. The nuclear hormone receptor oestrogen-related receptor γ (ERRγ) is a constitutively active transcriptional activator regulating gene expression.
  
  
  OBJECTIVE
  To investigate the role of ERRγ in the alcohol-mediated regulation of CYP2E1 and to examine the possibility to control alcohol-mediated oxidative stress and liver injury through an ERRγ inverse agonist.
  
  
  METHODS
  For chronic alcoholic hepatosteatosis study, C57BL/6J wild-type and CB1(-/-) mice were administered alcohol for 4 weeks. GSK5182 and chlormethiazole (CMZ) were given by oral gavage for the last 2 weeks of alcohol feeding. Gene expression profiles and biochemical assays were performed using the liver or blood of mice.
  
  
  RESULTS
  Hepatic ERRγ gene expression induced by alcohol-mediated activation of CB1 receptor results in induction of CYP2E1, while liver-specific ablation of ERRγ gene expression blocks alcohol-induced expression of CYP2E1 in mouse liver. An ERRγ inverse agonist significantly ameliorates chronic alcohol-induced liver injury in mice through inhibition of CYP2E1-mediated generation of ROS, while inhibition of CYP2E1 by CMZ abrogates the beneficial effects of the inverse agonist. Finally, chronic alcohol-mediated ERRγ and CYP2E1 gene expression, ROS generation and liver injury in normal mice were nearly abolished in CB1(-/-) mice.
  
  
  CONCLUSIONS
  ERRγ, as a previously unrecognised transcriptional regulator of hepatic CB1 receptor, controls alcohol-induced oxidative stress and liver injury through CYP2E1 induction, and its inverse agonist could ameliorate oxidative liver injury due to chronic alcohol exposure.
authors.affiliation: National Creative Research Initiatives Center for Nuclear Receptor Signals, Hormone Research Center, Gwangju, Republic of Korea.|School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Don-Kyu
authors.initials: DK
authors.lastname: Kim
authors.affiliation: Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
authors.forename: Yong-Hoon
authors.initials: YH
authors.lastname: Kim
authors.affiliation: School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Hyun-Hee
authors.initials: HH
authors.lastname: Jang
authors.affiliation: Department of Molecular Cell Biology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi-do, Republic of Korea.
authors.forename: Jinyoung
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Life Science, Gachon University, Sungnam, Gyeonggi-do, Republic of Korea.
authors.forename: Jung Ran
authors.initials: JR
authors.lastname: Kim
authors.affiliation: Department of Chemistry, Seoul National University, Seoul, Republic of Korea.
authors.forename: Minseob
authors.initials: M
authors.lastname: Koh
authors.affiliation: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
authors.forename: Won-Il
authors.initials: WI
authors.lastname: Jeong
authors.affiliation: Department of Molecular Cell Biology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi-do, Republic of Korea.
authors.forename: Seung-Hoi
authors.initials: SH
authors.lastname: Koo
authors.affiliation: Department of Life Science, Gachon University, Sungnam, Gyeonggi-do, Republic of Korea.
authors.forename: Tae-Sik
authors.initials: TS
authors.lastname: Park
authors.affiliation: School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Chul-Ho
authors.initials: CH
authors.lastname: Yun
authors.affiliation: Department of Chemistry, Seoul National University, Seoul, Republic of Korea.|Department of Biophysics and Chemical Biology, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea.
authors.forename: Seung Bum
authors.initials: SB
authors.lastname: Park
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, USA.
authors.forename: John Y L
authors.initials: JYL
authors.lastname: Chiang
authors.affiliation: Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
authors.forename: Chul-Ho
authors.initials: CH
authors.lastname: Lee
authors.affiliation: National Creative Research Initiatives Center for Nuclear Receptor Signals, Hormone Research Center, Gwangju, Republic of Korea.|School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.|Department of Biomedical Sciences, Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Hueng-Sik
authors.initials: HS
authors.lastname: Choi
mesh_terms: D000818:Animals; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism*; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000431:Ethanol / Q000494:pharmacology; D020869:Gene Expression Profiling / Q000379:methods; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D008099:Liver / Q000378:metabolism; D008108:Liver Diseases, Alcoholic / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology; D043884:Receptor, Cannabinoid, CB1 / Q000502:physiology*; D011960:Receptors, Estrogen / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D014158:Transcription, Genetic / Q000502:physiology
chemical_list: D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004791:Enzyme Inhibitors; C490916:Esrrg protein, mouse; C583041:GSK5182; D043884:Receptor, Cannabinoid, CB1; D011960:Receptors, Estrogen; D013629:Tamoxifen; D000431:Ethanol; D019392:Cytochrome P-450 CYP2E1