Eicosapentaenoic acid (EPA) in fish oil is known to improve hepatic steatosis. However, it remains unclear whether such action of EPA is actually caused by peroxisome proliferator-activated receptor α (PPARα) activation. To explore the contribution of PPARα to the effects of EPA itself, male wild-type and Ppara-null mice were fed a saturated fat diet for 16 weeks, and highly (>98%)-purified EPA was administered in the last 12 weeks. Furthermore, the changes caused by EPA treatment were compared to those elicited by fenofibrate (FF), a typical PPARα activator. A saturated fat diet caused macrovesicular steatosis in both genotypes. However, EPA ameliorated steatosis only in wild-type mice without PPARα activation, which was evidently different from numerous previous observations. Instead, EPA inhibited maturation of sterol-responsive element-binding protein (SREBP)-1 in the presence of PPARα through down-regulation of SREBP cleavage-activating protein and site-1 protease. Additionally, EPA suppressed fatty acid uptake and promoted hydrolysis of intrahepatic triglycerides in a PPARα-independent manner. These effects were distinct from those of fenofibrate. Although fenofibrate induced NAPDH oxidase and acyl-coenzyme A oxidase and significantly increased hepatic lipid peroxides, EPA caused PPARα-dependent induction of superoxide dismutases, probably contributing to a decrease in the lipid peroxides. These results firstly demonstrate detailed mechanisms of steatosis-ameliorating effects of EPA without PPARα activation and ensuing augmentation of hepatic oxidative stress.
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