DOCOSAHEXAENOIC AND EICOSAPENTAENOIC ACIDS ARE DIFFERENTLY METABOLIZED IN RAT-LIVER DURING MITOCHONDRIA AND PEROXISOME PROLIFERATION

The 3-thia fatty acids, tetradecylthioacetic acid and 3,10-dithiadicar boxylic acid are mitochondrion and peroxisome proliferators. Administr ation of these promotes an increased transport of endogenous fatty aci ds to these organelles and a higher capacity of beta-oxidation. Admini stration of 3-thia fatty acids to rats resulted in a significant decre ase of the hepatic level of docosahexaenoic acid (DHA) (17-24%) and es pecially eicosapentaenoic acid (EPA) (40-80%) accompanied by increased gene expression of mitochondrial 2,4-dienoyl-CoA reductase and enoyl- CoA isomerase. The mitochondrial oxidation of EPA was increased more t han 4-fold after administration of 3-thia fatty acids. EPA-CoA was a g ood substrate for mitochondrial carnitine acyltransferase-I and treatm ent with 3-thia fatty acids increased the activity 1.7-fold. DHA was a poor substrate for both mitochondrial and peroxisomal beta-oxidation. DHA-CoA was a very poor substrate for mitochondrial carnitine acyltra nsferase-I and -II, and the activity did not increase after treatment. However, the peroxisomal DHA-CoA oxidase increased 10-fold after 3-th ia fatty acid treat ment, whereas the peroxisomal EPA-CoA oxidase incr eased only 5-fold. In isolated hepatocytes, 16% of total metabolized E PA was oxidized and 76% was incorporated into glycerolipids, whereas D HA was oxidized very little. We conclude that under conditions of incr eased mitochondrial and peroxisomal proliferation by 3-thia fatty acid s, a relatively higher-oxidation rate of polyunsaturated n-3 fatty aci ds might result in a decreased hepatic level of EPA and DHA. Under the se conditions DHA seems to be oxidized by the peroxisomes, Whereas EPA , which can be oxidized in both or organelles, is mainly oxidized by m itochondria.