1. Soluble Epoxide Hydrolase Hepatic Deficiency Ameliorates Alcohol-Associated Liver Disease
- Author
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Bruce D. Hammock, A. F. S. Mello, Natalie J. Török, Fawaz G. Haj, Jun Yang, Ming-Fo Hsu, Bryan Chu, Christophe Morisseau, Jeff Cheng, and Shinichiro Koike
- Subjects
Steatosis ,Soluble Epoxide Hydrolase ,Injury ,Pharmacology ,Alcohol-Associated Liver Disease ,Transgenic ,Alcohol Use and Health ,Substance Misuse ,Mice ,0302 clinical medicine ,Hepatocyte ,Aetiology ,Original Research ,chemistry.chemical_classification ,Epoxide Hydrolases ,EpETE, epoxyeicosatetraenoic acid ,LC, liquid chromatography ,Liver Diseases ,Liver Disease ,Gastroenterology ,EpDPE, epoxydocosapentaenoic acid ,Alcoholic ,DiHDPE, dihydroxydocosapentaenoic acid ,EpODE, epoxyoctadecadienoic acid ,cardiovascular system ,CYP, cytochrome P450 ,030211 gastroenterology & hepatology ,Epoxide hydrolase 2 ,PPARγ, peroxisome proliferator-activated receptor-γ ,SOD-1, superoxide dismutase-1 ,eIF2α, eukaryotic initiation factor 2α ,ADH, alcohol dehydrogenase ,03 medical and health sciences ,4-HNE, 4-hydroxynonenal ,Liver Diseases, Alcoholic ,EpFA, epoxy fatty acid ,IRE1α, inositol-requiring enzyme-1α ,MS, mass spectroscopy ,Ethanol ,Animal ,medicine.disease ,sEH, soluble epoxide hydrolase ,030104 developmental biology ,ALDH, aldehyde dehydrogenase ,chemistry ,EpETrE, epoxyeicosatrienoic acid ,Drug Evaluation ,Digestive Diseases ,0301 basic medicine ,TNFα, tumor necrosis factor-α ,NOX, nicotinamide adenine dinucleotide phosphate oxidase ,Drug Evaluation, Preclinical ,DMSO, dimethyl sulfoxide ,medicine.disease_cause ,Oral and gastrointestinal ,Liver disease ,Piperidines ,Pharmacologic Inhibition ,2.1 Biological and endogenous factors ,IL1β, interleukin 1β ,eNOS, endothelial nitric oxide synthase ,Preclinical ,mRNA, messenger RNA ,Alcoholism ,medicine.anatomical_structure ,Liver ,Female ,medicine.symptom ,Chronic Liver Disease and Cirrhosis ,NF-κB, nuclear factor-κB ,Inflammation ,Mice, Transgenic ,Stress ,ER, endoplasmic reticulum ,ROS, reactive oxygen species ,ALT, alanine aminotransferase ,HETE, hydroxyeicosatetraenoic acid ,ALD, alcohol-associated liver disease ,medicine ,Animals ,lcsh:RC799-869 ,Nutrition ,EETs, epoxyeicosatrienoic acids ,TPPU, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea ,Hepatology ,business.industry ,PERK, protein kinase R-like ER kinase ,Phenylurea Compounds ,Lipid signaling ,Disease Models, Animal ,Enzyme ,Good Health and Well Being ,Gene Expression Regulation ,Disease Models ,lcsh:Diseases of the digestive system. Gastroenterology ,business ,Oxidative stress - Abstract
Background & Aims Alcohol-associated liver disease (ALD) is a significant cause of liver-related morbidity and mortality worldwide and with limited therapies. Soluble epoxide hydrolase (sEH; Ephx2) is a largely cytosolic enzyme that is highly expressed in the liver and is implicated in hepatic function, but its role in ALD is mostly unexplored. Methods To decipher the role of hepatic sEH in ALD, we generated mice with liver-specific sEH disruption (Alb-Cre; Ephx2fl/fl). Alb-Cre; Ephx2fl/fl and control (Ephx2fl/fl) mice were subjected to an ethanol challenge using the chronic plus binge model of ALD and hepatic injury, inflammation, and steatosis were evaluated under pair-fed and ethanol-fed states. In addition, we investigated the capacity of pharmacologic inhibition of sEH in the chronic plus binge mouse model. Results We observed an increase of hepatic sEH in mice upon ethanol consumption, suggesting that dysregulated hepatic sEH expression might be involved in ALD. Alb-Cre; Ephx2fl/fl mice presented efficient deletion of hepatic sEH with corresponding attenuation in sEH activity and alteration in the lipid epoxide/diol ratio. Consistently, hepatic sEH deficiency ameliorated ethanol-induced hepatic injury, inflammation, and steatosis. In addition, targeted metabolomics identified lipid mediators that were impacted significantly by hepatic sEH deficiency. Moreover, hepatic sEH deficiency was associated with a significant attenuation of ethanol-induced hepatic endoplasmic reticulum and oxidative stress. Notably, pharmacologic inhibition of sEH recapitulated the effects of hepatic sEH deficiency and abrogated injury, inflammation, and steatosis caused by ethanol feeding. Conclusions These findings elucidated a role for sEH in ALD and validated a pharmacologic inhibitor of this enzyme in a preclinical mouse model as a potential therapeutic approach., Graphical abstract
- Published
- 2021