Soluble epoxide hydrolase inhibition: a novel therapeutic strategy in alcoholic liver disease.

Abstract

Emerging evidence suggests that soluble epoxide hydrolase (sEH) inhibition is a valuable therapeutic strategy for the treatment of numerous diseases. sEH rapidly degrades cytochrome P450-produced epoxygenated lipids (epoxy-fatty acids, epFAs), which generally exert beneficial effects on several cellular processes. sEH hydrolysis of epoxy-fatty acids produces dihydroxy-fatty acids which are typically less biologically active than their parent epoxide. sEH inhibition has shown efficacy in treating numerous pathologies associated with non-alcoholic liver disease, yet no efforts to date have tested the efficacy of sEH inhibition in alcoholic liver disease (ALD). Herein, we measured the levels of sEH expression and epFAs in human ALD, and assessed the efficacy of the sEH inhibitor t-TUCB in multiple pre-clinical mouse models of ALD. Mice exposed to ethanol but treated with t-TUCB had decreased liver injury, inflammation, and endoplasmic reticulum (ER) stress compared to controls, an observation that was reproduced in whole-body sEH knockout mice. In vitro, individual epFAs (17,18-EpETE and 19,20-EpDPA) prevented hepatocyte apoptosis/ER stress and endotoxin-induced pro-inflammatory cytokine production in macrophages. These results suggest the ability of sEH inhibition to prevent alcohol-associated liver injury, inflammation, and ER stress, that is potentially mediated by specific epFAs. Future work will determine the efficacy of sEH inhibition in a treatment paradigm of sEH inhibitor administration and further elucidate molecular mechanisms.