Estrogen-related receptor γ controls hepatic CB1 receptor-mediated CYP2E1 expression and oxidative liver injury by alcohol

Don Kyu Kim, Yong Hoon Kim, Hyun Hee Jang, Jinyoung Park, Jung Ran Kim, Minseob Koh, Won Il Jeong, Seung-Hoi Koo, Tae Sik Park, Chul Ho Yun, Seung Bum Park, John Y L Chiang, Chul Ho Lee, Hueng Sik Choi

Research output: Contribution to journalArticle

35 Citations (Scopus)


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 (ERR̃) is a constitutively active transcriptional activator regulating gene expression. Objective: To investigate the role of ERRã 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 bene ficial 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.

Original languageEnglish
Pages (from-to)1044-1054
Number of pages11
Issue number7
Publication statusPublished - 2013 Jul 1
Externally publishedYes

ASJC Scopus subject areas

  • Gastroenterology

Fingerprint Dive into the research topics of 'Estrogen-related receptor γ controls hepatic CB<sub>1</sub> receptor-mediated CYP2E1 expression and oxidative liver injury by alcohol'. Together they form a unique fingerprint.

  • Cite this

    Kim, D. K., Kim, Y. H., Jang, H. H., Park, J., Kim, J. R., Koh, M., Jeong, W. I., Koo, S-H., Park, T. S., Yun, C. H., Park, S. B., Chiang, J. Y. L., Lee, C. H., & Choi, H. S. (2013). Estrogen-related receptor γ controls hepatic CB1 receptor-mediated CYP2E1 expression and oxidative liver injury by alcohol. Gut, 62(7), 1044-1054.