Peroxisome proliferator-activated receptor α is not rate-limiting for the lipoprotein-lowering action of fish oil

Similar to fibrate hypolipidemic drugs, long chain polyunsaturated fatty acids contained in fish oil are activators of peroxisome proliferator-activated receptor alpha (PPAR alpha), The goal of this study was to assess the contribution of PPAR alpha in mediating the effect of fish oil on plasma lipid, lipoprotein, and apolipoprotein levels. To this end, PPAR alpha -deficient mice and wild-type littermates were fed isocaloric fish oil or coconut oil diets, the content of which varied reciprocally between 0, 3, 7, and 10% for 1 week. In both wild-type and PPAR alpha -deficient mice, fish oil feeding was associated with a dose-dependent decrease in triglycerides, cholesterol, and phospholipids associated with lower levels of very low density lipoprotein (VLDL) triglycerides and high density lipoprotein (HDL) cholesterol, The lowering of triglycerides and VLDL triglycerides was associated with a significant decrease of plasma apoC-III in both genotypes, Fish oil treatment did not influence hepatic apoC-III mRNA levels in either genotype indicating that apoC-III is not under transcriptional control by fish oil. The lowering of HDL cholesterol observed in both genotypes was associated with reduced plasma apoA-II without changes in liver apoA-II mRNA levels. In contrast, plasma apoA-I and liver apoA-I mRNA levels were decreased in wild-type but not in PPAR alpha -deficient mice after fish oil feeding indicating that PPAR alpha contributes to the effect of fish oil on apoA-I gene expression. In conclusion, PPAR alpha is not rate-limiting for fish oil to exert its triglyceride- and HDL-lowering action. Furthermore, PPAR alpha mediates, at least partly, the decrease of apoA-I after fish oil treatment, whereas apoC-III and apoA-II levels are affected in a PPAR alpha -independent manner. Altogether, these results show major molecular differences in action between fibrates and fish oil providing a molecular rationale for combination treatment with these compounds.