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Estrogen-related receptor γ controls hepatic CB1 receptor-mediated CYP2E1 expression and oxidative liver injury by alcohol
  1. Don-Kyu Kim1,2,
  2. Yong-Hoon Kim3,
  3. Hyun-Hee Jang2,
  4. Jinyoung Park4,
  5. Jung Ran Kim5,
  6. Minseob Koh6,
  7. Won-Il Jeong7,
  8. Seung-Hoi Koo4,
  9. Tae-Sik Park5,
  10. Chul-Ho Yun2,
  11. Seung Bum Park6,8,
  12. John Y L Chiang9,
  13. Chul-Ho Lee3,
  14. Hueng-Sik Choi1,2,10
  1. 1National Creative Research Initiatives Center for Nuclear Receptor Signals, Hormone Research Center, Gwangju, Republic of Korea
  2. 2School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea
  3. 3Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea
  4. 4Department of Molecular Cell Biology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi-do, Republic of Korea
  5. 5Department of Life Science, Gachon University, Sungnam, Gyeonggi-do, Republic of Korea
  6. 6Department of Chemistry, Seoul National University, Seoul, Republic of Korea
  7. 7Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
  8. 8Department of Biophysics and Chemical Biology, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea
  9. 9Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, USA
  10. 10Department of Biomedical Sciences, Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju, Republic of Korea
  1. Correspondence to Professor Hueng-Sik Choi, Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea; hsc{at}chonnam.ac.kr; Dr Chul-Ho Lee, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Republic of Korea; chullee{at}kribb.re.kr

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.

Design 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.

  • Alcohol-Induced Injury
  • Alcoholic Liver Disease
  • Liver
  • Liver Metabolism
  • Gene Regulation

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