Dietary C20–22 ω3 PUFA regulate hepatic oxidized PUFA levels and attenuate markers of diet induced non‐alcoholic steatohepatitis (NASH) in Ldlr−/− mice

Abstract

Non‐alcoholic steatohepatitis (NASH) is a progressive form of fatty liver disease that is characterized by hepatic inflammation, oxidative stress and fibrosis. The capacity of eicosapentaenoic acid (20:5ω3; EPA) and docosahexaenoic acid (22:6ω3; DHA) to attenuate diet‐induced NASH was examined in Ldlr−/− mice fed a western diet (WD) for 16 weeks. The WD induced severe hepatosteatosis, inflammation (Mcp1), oxidative stress (NADPH oxidase, Nox2), and fibrosis (Procol1α1). The WD also increased hepatic ω6 PUFA (i.e., arachidonic acid, 20:4ω6) & COX/LOX derived oxidized PUFA (oxPUFA, i.e., 6‐keto‐PGF1α; 12‐HETE). Mice fed the WD containing EPA or DHA had decreased expression of NASH markers (Mcp1, Nox2, Procol1α1), hepatic ω6 PUFA & ω6 oxPUFA, but increased hepatic content of ω3 PUFA & oxPUFA, i.e., EPA, DHA, 18‐HEPE & 17,18‐DiHETE. 18‐HEPE is a resolvin E‐series precursor and 17,18‐DiHETE is an epoxide hydrolase product of 17,18 epoxy‐eicosatetraenoic acid; these are cytoprotective fatty acids. We speculate that oxidized products of hepatic C20–22 ω3 PUFA metabolism play a role in the ω3 PUFA attenuation of inflammation, fibrosis and oxidative stress in WD‐induced NASH in Ldlr−/− mice.Grant Funding Source: NIFA/USDA (2009–65200‐05846) and NIH (DK 094600 and DK043220)