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

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35 Citations (Scopus)

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 (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
JournalGut
Volume62
Issue number7
DOIs
Publication statusPublished - 2013 Jul
Externally publishedYes

ASJC Scopus subject areas

  • Gastroenterology

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    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. https://doi.org/10.1136/gutjnl-2012-303347