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

Abstract

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.

Regulation of inflammatory and lipid metabolism genes by eicosapentaenoic acid-rich oil

“…Despite this choice of model, many of the genes regulated by EO were involved in cholesterol, sterol, and lipid metabolism. This is consistent with clinical observations whereby the predominant effect of 3-PUFA dietary supplementation is the lowering of circulating triglyceride levels (24)(25)(26)(27). In fact, the lipid-lowering effect is often seen in the absence of an anti-infl ammatory response ( 28 ).…”

Polymorphisms, de novo lipogenesis, and plasma triglyceride response following fish oil supplementation

“…Intracellular TG can then be mobilized in the cytosol by lipolysis, followed by reesterifi cation through a delayed pathway, also contributing to VLDL-TG production ( 38, 39 ). As described earlier, n-3 PUFA consumption induces a decrease in de novo lipogenesis mediated by SREBF1 gene (9)(10)(11)40 ). In the literature, two SNPs within SREBF1 gene (rs2297508 and rs1889018) have been associated with a modest increase of type 2 diabetes risk, body weight (BMI or obesity), total-C, LDL-C, and plasma TG concentrations ( 14,16,41,42 ).…”

Omega-3 Fatty Acid Improve Non Alcoholic Fatty Liver Induced by High Fat Diet in Rats.

“…This could be explained by changes in transcription of several nuclear receptors are reported to mediate the TG-reducing effects of omega-3 fatty acid: sterol regulatory element binding proteins (SREBP), liver X receptor-alpha (LXRα), retinoid X receptor alpha (RXRα), farnesoid X receptor (FXR), and peroxisome proliferator-activated receptors (PPARs), and each play prominent roles in controlling lipid metabolism. Also the reduction of NEFA by omega-3 fatty acid due to suppressing in gene expression involved in new fatty acid synthesis and by inducing fatty acid oxidation in different tissues , such as, liver, skeletal muscle and white adipose tissue [28,29] …”