n-3 polyunsaturated fatty acids-enriched fish oil attenuates chronic alcohol-induced liver injury via a mechanism involving the upregulation of Retsat.

This study aimed to delineate the protective role of fish oil against alcoholic liver disease (ALD), identify the principal active component between eicosapentaenoic acid (EPA, C20:5 n-3) and docosahexaenoic acid (DHA, C22:6 n-3), and elucidate the molecular mechanisms. C57BL/6J mice were randomly assigned to receive either an alcohol-fed (AF) or pair-fed control (PF) diet, enriched with fish oil (FO) or corn oil (CO) for four weeks. Additionally, a series of in vitro experiments were performed using AML-12 cells to further investigate potential mechanisms. The results showed that plasma levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were significantly lower in the AF-FO group compared to the AF-CO group, indicating that fish oil alleviated alcohol-induced liver damage. Hepatic antioxidant markers, including glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) were also higher in the AF-FO group than in the AF-CO group. Transcriptomic analysis revealed FO supplementation significantly affected genes involved in oxidoreductase activity and lipid metabolism pathways, with Retsat being the most up-regulated gene. The in vitro experiments indicated that DHA, but not EPA, markedly increased Retsat expression, cell viability, and the expression of genes related to oxidoreductase activity and lipid metabolism, compared to linoleic acid (LA, C18:2 n-6). Notably, knocking down Retsat abolished the protective effects of DHA. In conclusion, dietary fish oil mitigated chronic alcohol-induced liver injury primarily through DHA by upregulating Retsat and downstream genes associated with oxidoreductase function and lipid metabolism.