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Soluble epoxide hydrolase hepatic deficiency ameliorates alcohol-associated liver disease.
Soluble epoxide hydrolase hepatic deficiency ameliorates alcohol-associated liver disease. Cellular and molecular gastroenterology and hepatology Mello, A., Hsu, M., Koike, S., Chu, B., Cheng, J., Yang, J., Morisseau, C., Torok, N. J., Hammock, B. D., Haj, F. G. 2020Abstract
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 has heretofore remained uncharted.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 evaluated under pair- and ethanol-fed states. Additionally, we investigated the capacity of pharmacological inhibition of sEH in the chronic plus binge mouse model.RESULTS: We observed elevation 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 the corresponding attenuation in the sEH activity and alteration in the lipid epoxide/diol ratio. Consistently, hepatic sEH deficiency ameliorated ethanol-induced hepatic injury, inflammation, and steatosis. Additionally, targeted metabolomics identified lipid mediators that were significantly impacted by hepatic sEH deficiency. Moreover, hepatic sEH deficiency was associated with a significant attenuation of ethanol-induced hepatic endoplasmic reticulum and oxidative stress. Notably, pharmacological 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 pharmacological inhibitor of this enzyme in a preclinical mouse model as a potential therapeutic approach.
View details for DOI 10.1016/j.jcmgh.2020.10.002
View details for PubMedID 33068774