Effect of soluble epoxide hydrolase inhibition on alcohol-associated liver disease
Background: Alcohol-associated liver disease (ALD) is a significant global health issue for which treatment regimens are limited and mostly ineffective, with no FDA-approved therapies.  Metabolism of polyunsaturated fatty acids (e.g. DHA and EPA) generates a class of beneficial, anti-inflammatory compounds, epoxy fatty acids (Ep-FAs), which are rapidly degraded into inactive diols through the action of soluble epoxide hydrolase (s-EH). Pharmacological inhibition of s-EH has proven effective in treating several conditions.  In the current study, the s-EH inhibitor, t-TUCB, was tested for efficacy in the treatment of ethanol-induced liver damage in in a mouse model of ALD resulting from chronic consumption of alcohol.   Methods:  C57BL6/J male mice were provided an all-liquid diet containing 5% (v/v) ethanol ± t-TUCB for 5 weeks. Liver pathology was assessed by multiple assays, targeted lipidomics of liver and intestine, and 16S sequencing  approaches were applied.  Results: Ethanol-induced plasma ALT activity was significantly decreased in t-TUCB-treated mice and steatosis was moderately reduced.  Hepatocyte cell death, ER stress, and the expression of pro-inflammatory cytokines were all reduced in mice treated with t-TUCB.  Underlying mechanisms driving the effect of s-EH inhibition include a shift in eicosanoid profiles to favor Ep-FAs, some of which were demonstrated to decrease apoptosis and LPS-stimulated cytokine expression in vitro. Analysis of the gut microbiota revealed significant changes resulting from ethanol alone, and by t-TUCB in pair-fed mice, with more limited effects found in ethanol-consuming mice treated with t-TUCB.  Conclusions: t-TUCB attenuated ethanol-induced liver injury via altering the lipidomic landscape in favor of Ep-FAs, but had limited affects on the gut microbiota.  These data suggest that s-EH inhibition may be a promising new target in the treatment and/or prevention of liver damage resulting from excessive alcohol consumption.