EICOSAPENTAENOIC ACID, BUT NOT DOCOSAHEXAENOIC ACID, INCREASES MITOCHONDRIAL FATTY-ACID OXIDATION AND UP-REGULATES 2,4-DIENOYL-COA REDUCTASE GENE-EXPRESSION IN RATS

The aim of the present study was to investigate whether eicosapentaeno ic acid (EPA) or docosahexaenoic acid (DHA) was responsible for the tr iglyceride-lowering effect of fish oil. In rats fed a single dose of E PA as ethyl ester (EPA-EE), the plasma concentration of triglycerides was decreased at 8 h after acute administration. This was accompanied by an increased hepatic fatty acid oxidation and mitochondrial 2,4-die noyl-CoA reductase activity. The steady-state level of 2,4-dienoyl-CoA reductase mRNA increased in parallel with the enzyme activity. An inc reased hepatic long-chain acyl-CoA content, but a reduced amount of he patic malonyl-CoA, was obtained at 8 h after acute EPA-EE treatment. O n EPA-EE supplementation, both EPA (20:5n-3) and docosapentaenoic acid (DPA, 22:5n-3) increased in the liver, whereas the hepatic DHA (22:6n -3) concentration was unchanged. On DHA-EE supplementation retroconver sion to EPA occurred. No statistically significant differences were fo und, however, for mitochondrial enzyme activities, malonyl-CoA, long-c hain acyl-CoA, plasma lipid levels, and the amount of cellular fatty a cids between DHA-EE treated rats and their controls at any time point studied. In cultured rat hepatocytes, the oxidation of [1-C-14]palmiti c acid was reduced by DHA, whereas it was stimulated by EPA. In the in vivo studies, the activities of phosphatidate phosphohydrolase and ac etyl-CoA carboxylase were unaffected after acute EPA-EE and DHA-EE adm inistration, but the fatty acyl-CoA oxidase, the rate-limiting enzyme in peroxisomal fatty acid oxidation, was increased after feeding these n-3 fatty acids. The hypocholesterolemic properties of EPA-EE may be due to decreased 3-hydroxy-3-methylglutaryl-CoA reductase activity. Fu rthermore, replacement of the ordinary fatty acids, i.e., the monoenes (16:1n-7, 18:1n-7, and 18:1n-9) with EPA and some conversion to DPA c oncomitant with increased fatty acid oxidation is probably the mechani sm leading to changed fatty acid composition. In contrast, DHA does no t stimulate fatty acid oxidation and, consequently, no such displaceme nt mechanism operates. in conclusion, we have obtained evidence that E PA, and not DHA, is the fatty acid primarily responsible for the trigl yceride-lowering effect of fish oil in rats.