Soluble Epoxide Hydrolase Hepatic Deficiency Ameliorates Alcohol-Associated Liver Disease

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; Ephx2 fl/fl ). Alb-Cre; Ephx2 fl/fl and control (Ephx2 fl/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; Ephx2 fl/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.

The zhuyu pill relieves rat cholestasis by regulating the mRNA expression of lipid and bile metabolism associated genes

“…Alox15 and Ephx2 are potential hub genes in bile acid metabolism, which correlates with liver function. The downregulation of these genes is shown to improve liver injury, inflammation, and steatosis ( Martínez-Clemente et al, 2010 ; Mello et al, 2021 ) and promote drug and fatty acid metabolism, thereby reducing liver toxicity ( Zhang et al, 2017 ; Almansour et al, 2018 ). The current study showed that Alox15 and Ephx2 expression were downregulated by ZYP, suggesting that this drug may inhibit inflammation and improve liver function.…”

Crosstalk between Depression and Breast Cancer via Hepatic Epoxide Metabolism: A Central Comorbidity Mechanism

“…The effects of depression on the liver are known to be reflected in inflammation, oxidative damage, and reduced immune surveillance [ 101 , 105 , 121 ]. From the perspective of molecular mechanisms, the upregulation of hepatic sEH is one of the pivotal upstream causes of liver damage, liver fibrosis, and hepatitis [ 101 , 122 , 123 , 124 ]. The inhibition of hepatic sEH significantly reduces endoplasmic reticulum stress in hepatocytes and maintains low expression of prostaglandins and triglycerides, thereby reducing high-fat-diet-induced inflammation [ 89 ].…”

Inhibition of Soluble Epoxide Hydrolase Activity by Components of Glycyrrhiza uralensis

“…In particular, sEH is an enzyme mainly expressed in the liver, and alcohol-induced inflammation, injury, and steatosis were reduced in hepatic sEH-knockout mice [ 10 ]. Moreover, an sEH inhibitor, PTUPB, inhibited the expression of TNF-a, MCP-1, and IL-6 in non-alcoholic fatty liver disease mice [ 11 ].…”

“…Moreover, an sEH inhibitor, PTUPB, inhibited the expression of TNF-a, MCP-1, and IL-6 in non-alcoholic fatty liver disease mice [ 11 ]. Therefore, sEH inhibition is known as a target enzyme to reduce the inflammatory response in alcohol- or non-alcohol-induced inflammation in the liver [ 10 , 11 ].…”