Title: Soluble Epoxide Hydrolase Hepatic Deficiency Ameliorates Alcohol-Associated Liver Disease.
Authors: Mello, Aline; Hsu, Ming-Fo; Koike, Shinichiro; Chu, Bryan; Cheng, Jeff; Yang, Jun; Morisseau, Christophe; Torok, Natalie J; Hammock, Bruce D; Haj, Fawaz G
Published In Cell Mol Gastroenterol Hepatol, (2021)
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.
PubMed ID: 33068774
MeSH Terms: Animals; Disease Models, Animal; Drug Evaluation, Preclinical; Epoxide Hydrolases/antagonists & inhibitors; Epoxide Hydrolases/genetics; Epoxide Hydrolases/metabolism*; Ethanol/administration & dosage; Ethanol/toxicity*; Female; Gene Expression Regulation/drug effects; Liver Diseases, Alcoholic/drug therapy; Liver Diseases, Alcoholic/etiology*; Liver Diseases, Alcoholic/pathology; Liver/enzymology; Liver/immunology; Liver/pathology*; Mice; Mice, Transgenic; Phenylurea Compounds/pharmacology; Phenylurea Compounds/therapeutic use*; Piperidines/pharmacology; Piperidines/therapeutic use*