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

30 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 1
Externally publishedYes

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Cannabinoid Receptor CB1
Cytochrome P-450 CYP2E1
Estrogen Receptors
Alcohols
Liver
Wounds and Injuries
Chlormethiazole
Gene Expression
Reactive Oxygen Species
Oxidative Stress
Endocannabinoids
Alcoholic Liver Diseases
Cytoplasmic and Nuclear Receptors
Transcriptome

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Kim, D. K., Kim, Y. H., Jang, H. H., Park, J., Kim, J. R., Koh, M., ... 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

Estrogen-related receptor γ controls hepatic CB1 receptor-mediated CYP2E1 expression and oxidative liver injury by alcohol. / Kim, Don Kyu; Kim, Yong Hoon; Jang, Hyun Hee; Park, Jinyoung; Kim, Jung Ran; Koh, Minseob; Jeong, Won Il; Koo, Seung-Hoi; Park, Tae Sik; Yun, Chul Ho; Park, Seung Bum; Chiang, John Y L; Lee, Chul Ho; Choi, Hueng Sik.

In: Gut, Vol. 62, No. 7, 01.07.2013, p. 1044-1054.

Research output: Contribution to journalArticle

Kim, DK, Kim, YH, Jang, HH, Park, J, Kim, JR, Koh, M, Jeong, WI, Koo, S-H, Park, TS, Yun, CH, Park, SB, Chiang, JYL, Lee, CH & Choi, HS 2013, 'Estrogen-related receptor γ controls hepatic CB1 receptor-mediated CYP2E1 expression and oxidative liver injury by alcohol', Gut, vol. 62, no. 7, pp. 1044-1054. https://doi.org/10.1136/gutjnl-2012-303347
Kim, Don Kyu ; Kim, Yong Hoon ; Jang, Hyun Hee ; Park, Jinyoung ; Kim, Jung Ran ; Koh, Minseob ; Jeong, Won Il ; Koo, Seung-Hoi ; Park, Tae Sik ; Yun, Chul Ho ; Park, Seung Bum ; Chiang, John Y L ; Lee, Chul Ho ; Choi, Hueng Sik. / Estrogen-related receptor γ controls hepatic CB1 receptor-mediated CYP2E1 expression and oxidative liver injury by alcohol. In: Gut. 2013 ; Vol. 62, No. 7. pp. 1044-1054.
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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 ERR{\~a} 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.",
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AU - Kim, Jung Ran

AU - Koh, Minseob

AU - Jeong, Won Il

AU - Koo, Seung-Hoi

AU - Park, Tae Sik

AU - Yun, Chul Ho

AU - Park, Seung Bum

AU - Chiang, John Y L

AU - Lee, Chul Ho

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