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<a href="http://doi.org/10.1136/gutjnl-2012-303347" target="_blank" rel="noreferrer noopener">http://doi.org/10.1136/gutjnl-2012-303347</a>
Pages
1044–1054
Issue
7
Volume
62
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Title
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Estrogen-related receptor gamma controls hepatic CB1 receptor-mediated CYP2E1 expression and oxidative liver injury by alcohol.
Publisher
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Gut
Date
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2013
2013-07
Subject
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Alcohol-Induced Injury; Alcoholic Liver Disease; Alcoholic/genetics/*metabolism/prevention & control; Animals; Cannabinoid; CB1/*physiology; Cytochrome P-450 CYP2E1 Inhibitors; Cytochrome P-450 CYP2E1/genetics/*metabolism; Enzyme Inhibitors/pharmacology/therapeutic use; Enzymologic/drug effects/physiology; Estrogen/deficiency/genetics/*physiology; Ethanol/pharmacology; Gene Expression Profiling/methods; Gene Expression Regulation; Gene Regulation; Genetic/physiology; Inbred C57BL; Knockout; Liver; Liver Diseases; Liver Metabolism; Liver/metabolism; Male; Mice; Oxidation-Reduction; Oxidative Stress/physiology; Receptor; Receptors; Signal Transduction/drug effects/physiology; Tamoxifen/analogs & derivatives/pharmacology/therapeutic use; Transcription
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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
Description
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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 gamma (ERRgamma) is a constitutively active transcriptional activator regulating gene expression. OBJECTIVE: To investigate the role of ERRgamma in the alcohol-mediated regulation of CYP2E1 and to examine the possibility to control alcohol-mediated oxidative stress and liver injury through an ERRgamma 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 ERRgamma gene expression induced by alcohol-mediated activation of CB1 receptor results in induction of CYP2E1, while liver-specific ablation of ERRgamma gene expression blocks alcohol-induced expression of CYP2E1 in mouse liver. An ERRgamma 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 ERRgamma and CYP2E1 gene expression, ROS generation and liver injury in normal mice were nearly abolished in CB1(-/-) mice. CONCLUSIONS: ERRgamma, 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.
Identifier
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<a href="http://doi.org/10.1136/gutjnl-2012-303347" target="_blank" rel="noreferrer noopener">10.1136/gutjnl-2012-303347</a>
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Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
2013
Alcohol-Induced Injury
Alcoholic Liver Disease
Alcoholic/genetics/*metabolism/prevention & control
Animals
Cannabinoid
CB1/*physiology
Chiang John Y L
Choi Hueng-Sik
Cytochrome P-450 CYP2E1 Inhibitors
Cytochrome P-450 CYP2E1/genetics/*metabolism
Department of Integrative Medical Sciences
Enzyme Inhibitors/pharmacology/therapeutic use
Enzymologic/drug effects/physiology
Estrogen/deficiency/genetics/*physiology
Ethanol/pharmacology
Gene Expression Profiling/methods
Gene Expression Regulation
Gene Regulation
Genetic/physiology
Gut
Inbred C57BL
Jang Hyun-Hee
Jeong Won-Il
Kim Don-Kyu
Kim Jung Ran
Kim Yong-Hoon
Knockout
Koh Minseob
Koo Seung-Hoi
Lee Chul-Ho
Liver
Liver Diseases
Liver Metabolism
Liver/metabolism
Male
Mice
NEOMED College of Medicine
Oxidation-Reduction
Oxidative Stress/physiology
Park Jinyoung
Park Seung Bum
Park Tae-Sik
Receptor
Receptors
Signal Transduction/drug effects/physiology
Tamoxifen/analogs & derivatives/pharmacology/therapeutic use
Transcription
Yun Chul-Ho