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-dithiadicarboxylic acid are mitochondrion and peroxisome proliferators. Administration of these promotes an increased transport of endogenous fatty acids to these organelles and a higher capacity of beta-oxidation. Administration of 3-thia fatty acids to rats resulted in a significant decrease of the hepatic level of docosahexaenoic acid (DHA) (17-24%) and especially 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 than 4-fold after administration of 3-thia fatty acids. EPA-CoA was a good substrate for mitochondrial carnitine acyltransferase-I and treatment 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 acyltransferase-I and -II, and the activity did not increase after treatment. However, the peroxisomal DHA-CoA oxidase increased 10-fold after 3-thia fatty acid treatment, whereas the peroxisomal EPA-CoA oxidase increased only 5-fold. In isolated hepatocytes, 16% of total metabolized EPA was oxidized and 76% was incorporated into glycerolipids, whereas DHA was oxidized very little. We conclude that under conditions of increased mitochondrial and peroxisomal proliferation by 3-thia fatty acids, a relatively higher oxidation rate of polyunsaturated n-3 fatty acids might result in a decreased hepatic level of EPA and DHA. Under these conditions DHA seems to be oxidized by the peroxisomes, whereas EPA, which can be oxidized in both organelles, is mainly oxidized by mitochondria.

A hypolipidemic peroxisome proliferating fatty acid induces polydispersity of rat liver mitochondria.

Primary rat hepatocyte cultures exposed to tetradecylthioacetic acid for periods up to 96 h significantly increased fatty acid oxidation and decreased triacylglycerol synthesis and secretion. During the same period the mean areal fraction (%) and polydispersity of both mitochondria and peroxisomes increased, indicating growth and proliferation. In rats fed tetradecylthioacetic acid for 12 weeks, the fatty acid oxidation increased with a concomitant hypolipidemic effect. In addition, the areal fraction of both mitochondria and peroxisomes increased significantly and the number of lipid droplets decreased. The results suggest that tetradecylthioacetic acid affects mitochondria and peroxisomes both in vitro and in vivo. It is concluded that tetradecylthioacetic acid reduces secretion of triacylglycerol from rat hepatocytes both in vitro and in vivo mainly by stimulating fatty acid oxidation.