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

Similar to fibrate hypolipidemic drugs, long chain polyunsaturated fatty ac ids contained in fish oil are activators of peroxisome proliferator-activat ed receptor alpha (PPAR alpha), The goal of this study was to assess the co ntribution of PPAR alpha in mediating the effect of fish oil on plasma lipi d, lipoprotein, and apolipoprotein levels. To this end, PPAR alpha -deficie nt mice and wild-type littermates were fed isocaloric fish oil or coconut o il 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 fee ding was associated with a dose-dependent decrease in triglycerides, choles terol, and phospholipids associated with lower levels of very low density l ipoprotein (VLDL) triglycerides and high density lipoprotein (HDL) choleste rol, The lowering of triglycerides and VLDL triglycerides was associated wi th a significant decrease of plasma apoC-III in both genotypes, Fish oil tr eatment did not influence hepatic apoC-III mRNA levels in either genotype i ndicating that apoC-III is not under transcriptional control by fish oil. T he lowering of HDL cholesterol observed in both genotypes was associated wi th 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 indicati ng that PPAR alpha contributes to the effect of fish oil on apoA-I gene exp ression. In conclusion, PPAR alpha is not rate-limiting for fish oil to exe rt its triglyceride- and HDL-lowering action. Furthermore, PPAR alpha media tes, at least partly, the decrease of apoA-I after fish oil treatment, wher eas apoC-III and apoA-II levels are affected in a PPAR alpha -independent m anner. Altogether, these results show major molecular differences in action between fibrates and fish oil providing a molecular rationale for combinat ion treatment with these compounds.