Eicosapentaenoic acid improves hepatic steatosis independent of PPARα activation through inhibition of SREBP-1 maturation in mice

Biochem Pharmacol. 2010 Nov 15;80(10):1601-12. doi: 10.1016/j.bcp.2010.07.031. Epub 2010 Aug 4.


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.

MeSH terms

  • Animals
  • Dietary Fats / administration & dosage
  • Dietary Fats / adverse effects
  • Disease Models, Animal
  • Eicosapentaenoic Acid / pharmacology
  • Eicosapentaenoic Acid / therapeutic use*
  • Fatty Liver / drug therapy*
  • Fatty Liver / etiology
  • Fatty Liver / metabolism
  • Fatty Liver / pathology
  • Fenofibrate / pharmacology
  • Genotype
  • Immunoblotting
  • Lipid Peroxidation / drug effects
  • Liver / drug effects
  • Liver / metabolism
  • Liver / pathology
  • Liver Function Tests
  • Male
  • Mice
  • Mice, Knockout
  • Oxidative Stress / drug effects
  • PPAR alpha / genetics
  • PPAR alpha / metabolism*
  • Sterol Regulatory Element Binding Protein 1 / antagonists & inhibitors*


  • Dietary Fats
  • PPAR alpha
  • Srebf1 protein, mouse
  • Sterol Regulatory Element Binding Protein 1
  • Eicosapentaenoic Acid
  • Fenofibrate