Abstract/Summary

The regulation by fibrates and dietary fatty acids of the hepatic gene expression of apolipoproteins (apo) A-I and A-11, the major protein constituents of high-density lipoproteins, as well as of acyl-CoA oxidase, the rate-limiting enzyme of the peroxisomal P-oxidation pathway, was studied in vivu in the rat and in vitru in primary cultures of rat hepatocytes. In primary hepatocytes, different fibrates decreased apo A-I and increased acyl-CoA oxidase mRNA levels, whereas apo A-I1 mRNA only decreased in level after treatment with fenofibric acid, but not after bezafibrate, gemfibrozil or Wy-14643 treatment. Treat- ment with fenofibric acid counteracted the increase in apo A-I mRNA levels observed after dexametha- sone or all-trans retinoic acid treatment, whereas simultaneous addition of fenofibric acid together with all-trans retinoic acid or dexamethasone resulted in a superinduction of acyl-CoA oxidase mRNA. Addi- tion of the n-3 polyunsaturated fatty acids (PUFAs), docosanohexaenoic acid and eicosanopentaenoic acid, or the fatty acid derivative a-bromopalmitate, decreased apo A-I and increased acyl-CoA oxidase mRNA in a dose-dependent and time-dependent manner, whereas apo A-I1 mRNA did not change signifi- cantly. Nuclear run-on experiments demonstrated that fenofibric acid and a-bromopalmitate decreased apo A-I and increased acyl-CoA oxidase gene expression at the transcriptional level. When rats were fed isocaloric diets enriched in saturated fat (hydrogenated coconut oil), n-6 PUFAs (safflower oil) or n-3 PUFAs (fish oil), a significant decrease in liver apo A-I and apo A-I1 mRNA levels was only observed after fish oil feeding. Compared to feeding low fat, liver acyl-CoA oxidase mRNA increased after fat feeding, but this effect was most pronounced (twofold) in rats fed fish oil. Results from these studies indicate that fish oil feeding reduces rat liver apo A-I and apo A-I1 gene expression, similar to results obtained after feeding fenofibrate. Fibrates and n-3 fatty acids (and the fatty acid derivative, a-bromopal- mitate) down-regulate apo A-I and induce acyl-CoA oxidase gene expression through a direct transcrip- tional action on the hepatocyte. In contrast, only fenofibric acid, but not the other fibrates or fatty acids tested, decrease apo A-I1 gene expression in vitro.