REGULATION OF RAT-LIVER APOLIPOPROTEIN-A-I, APOLIPOPROTEIN-A-II AND ACYL-COENZYME-A OXIDASE GENE-EXPRESSION BY FIBRATES AND DIETARY FATTY-ACIDS

The regulation by fibrates and dietary fatty acids of the hepatic gene expression of apolipoproteins (apo) A-I and A-II, the major protein c onstituents of high-density lipoproteins, as well as of acyl-CoA oxida se, the rate-limiting enzyme of the peroxisomal beta-oxidation pathway , was studied in vivo in the rat and in vitro in primary cultures of r at hepatocytes. In primary hepatocytes, different fibrates decreased a po A-I and increased acyl-CoA oxidase mRNA levels, whereas apo A-Il mR NA only decreased in level after treatment with fenofibric acid, but n ot after bezafibrate, gemfibrozil or Wy-14643 treatment. Treatment wit h fenofibric acid counteracted the increase in apo A-I mRNA levels obs erved after dexamethasone or all-trans retinoic acid treatment, wherea s simultaneous addition of fenofibric acid together with all-trans ret inoic acid or dexamethasone resulted in a superinduction of acyl-CoA o xidase mRNA. Addition of the n-3 polyunsaturated fatty acids (PUFAs), docosanohexaenoic acid and eicosanopentaenoic acid, or the fatty acid derivative alpha-bromopalmitate, decreased apo A-I and increased acyl- CoA oxidase mRNA in a dose-dependent and time-dependent manner, wherea s apo A-II mRNA did not change significantly. Nuclear run-on experimen ts demonstrated that fenofibric acid and alpha-bromopalmitate decrease d apo A-I and increased acyl-CoA oxidase gene expression at the transc riptional level. When rats were fed isocaloric diets enriched in satur ated 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-II mRNA levels was only observed after fish oil feeding. Compared to fee ding Low fat, liver acyl-CoA oxidase mRNA increased after fat feeding, but this effect was most pronounced (twofold) in rats fed fish oil. R esults from these studies indicate that fish oil feeding reduces rat l iver apo A-I and apo A-II gene expression, similar to results obtained after feeding fenofibrate. Fibrates and n-3 fatty acids (and the fatt y acid derivative, alpha-bromopalmitate) down-regulate apo A-I and ind uce acyl-CoA oxidase gene expression through a direct transcriptional action on the hepatocyte. In contrast, only fenofibric acid, but not t he other fibrates or fatty acids tested, decrease apo A-II, gene expre ssion in vitro.