In contrast with docosahexaenoic acid, eicosapentaenoic acid and hypolipidaemic derivatives decrease hepatic synthesis and secretion of triacylglycerol by decreased diacylglycerol acyltransferase activity and stimulation of fatty acid oxidation

Hypolipidaemic fatty acid derivatives and polyunsaturated fatty acids decre ase concentrations of plasma triacylglycerol by mechanisms that are not ful ly understood. Because poor susceptibility to beta- and/or omega-oxidation is apparently a determinant of the peroxisome proliferating and hypolipidae mic capacity of fatty acids and derivatives, the relative importance of act ivation of the peroxisome-proliferator-activated receptor alpha (PPAR alpha ), fatty acid oxidation and triacylglycerol synthesis were examined. We hav e compared the effects of differentially beta-oxidizable fatty acids on the se parameters in primary cultures of rat hepatocytes. Tetradecylthioacetic acid (TTA), 2-methyleicosapentaenoic acid and 3-thia-octadecatetraenoic aci d, which are non-beta-oxidizable fatty acid derivatives, were potent activa tors of a glucocorticoid receptor (GR)-PPAR alpha chimaera. This activation was paradoxically reflected in an substantially increased oxidation of [1- C-14]palmitic acid and/or oleic acid. The incorporation of [1-C-14]palmitic acid and/or oleic acid into cell-associated and secreted triacylglycerol w as decreased by 15-20% and 30% respectively with these non-beta-oxidizable fatty acid derivatives. The CoA ester of TTA inhibited the esterification o f 1,2-diacylglycerol in rat liver microsomes. Both eicosapentaenoic acid (E PA) and docosahexaenoic acid (DHA) activated GR-PPAR alpha. EPA increased t he oxidation of [1-C-14]palmitic acid but DHA had no effect. The CoA ester of EPA inhibited the esterification of 1,2-diacylglycerol, whereas DHA-CoA had no effect. The ratio between synthesized triacylglycerol and diacylglyc erol was lower in hepatocytes cultured with EPA in the medium compared with DHA or oleic acid, indicating a decreased conversion of diacylglycerol to triacylglycerol. Indeed, the incorporation of [1-C-14]oleic acid into secre ted triacylglycerol was decreased by 20% in the presence of EPA. In conclus ion, a decreased availability of fatty acids for triacylglycerol synthesis by increased mitochondrial beta-oxidation and decreased triacylglycerol for mation caused by inhibition of diacylglycerol acyltransferase might explain the hypolipidaemic effect of TTA and EPA.