Soluble Epoxide Hydrolase Hepatic Deficiency Ameliorates Alcohol-Associated Liver Disease

Cell Mol Gastroenterol Hepatol. 2021;11(3):815-830. doi: 10.1016/j.jcmgh.2020.10.002. Epub 2020 Oct 15.

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.

Keywords: Alcohol-Associated Liver Disease; Hepatocyte; Inflammation; Injury; Pharmacologic Inhibition; Soluble Epoxide Hydrolase; Steatosis; Stress.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

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 / enzymology
  • Liver / immunology
  • Liver / pathology*
  • Liver Diseases, Alcoholic / drug therapy
  • Liver Diseases, Alcoholic / etiology*
  • Liver Diseases, Alcoholic / pathology
  • Mice
  • Mice, Transgenic
  • Phenylurea Compounds / pharmacology
  • Phenylurea Compounds / therapeutic use*
  • Piperidines / pharmacology
  • Piperidines / therapeutic use*

Substances

  • 1-trifluoromethoxyphenyl-3-(1-propionylpiperidine-4-yl)urea
  • Phenylurea Compounds
  • Piperidines
  • Ethanol
  • Epoxide Hydrolases
  • Ephx2 protein, mouse