THE HYPOTRIGLYCERIDEMIC EFFECT OF EICOSAPENTAENOIC ACID IN RATS IS REFLECTED IN INCREASED MITOCHONDRIAL FATTY-ACID OXIDATION FOLLOWED BY DIMINISHED LIPOGENESIS

The effect of eicosapentaenoic acid (EPA) on fatty acid oxidation and on key enzymes of triglyceride metabolism and lipogenesis was investig ated in the liver of rats. Repeated administration of EPA to normolipi demic rats resulted in a time-dependent decrease in plasma triglycerid es, phospholipids and cholesterol. The triglyceride-lowering effect wa s observed after one day of feeding whereas lowering of plasma cholest erol and phospholipids was observed after five days of treatment. The triglyceride content of liver was reduced after two-day treatment. At that time, increased mitochondrial fatty acid oxidation occurred where as mitochondrial and microsomal glycerophosphate acyltransferase was i nhibited. The phosphatidate phosphohydrolase activity was unchanged. A denosine triphosphate:citrate lyase, acetyl-CoA carboxylase, fatty aci d synthetase and glucose-6-phosphate dehydrogenase were inhibited duri ng the 15 d of EPA treatment whereas peroxisomal beta-oxidation was in creased. At one day of feeding, however, when the hypotriglyceridemic effect was established, the lipogenic enzyme activities were reduced t o the same extent in palmitic acid-treated animals as in EPA-treated r ats. In cultured rat hepatocytes, the oxidation of [C-14]palmitic acid to carbon dioxide and acid-soluble products was stimulated in the pre sence of EPA. These results suggest that the instant hypolipidemia in rats given EPA could be explained at least in part by a sudden increas e in mitochondrial fatty acid oxidation, thereby reducing the availabi lity of fatty acids for lipid synthesis in the liver for export, e.g., in the form of very low density lipoproteins, even before EPA induced peroxisomal fatty acid oxidation, reduced triglyceride biosynthesis a nd diminished lipogenesis.