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 decrease concentrations of plasma triacylglycerol by mechanisms that are not fully understood. Because poor susceptibility to β- and/or ω-oxidation is apparently a determinant of the peroxisome proliferating and hypolipidaemic capacity of fatty acids and derivatives, the relative importance of activation of the peroxisome-proliferator-activated receptor α (PPARα), fatty acid oxidation and triacylglycerol synthesis were examined. We have compared the effects of differentially β-oxidizable fatty acids on these parameters in primary cultures of rat hepatocytes. Tetradecylthioacetic acid (TTA), 2-methyleicosapentaenoic acid and 3-thia-octadecatetraenoic acid, which are non-β-oxidizable fatty acid derivatives, were potent activators of a glucocorticoid receptor (GR)-PPARα chimaera. This activation was paradoxically reflected in an substantially increased oxidation of [1-¹⁴C]palmitic acid and/or oleic acid. The incorporation of [1-¹⁴C]palmitic acid and/or oleic acid into cell-associated and secreted triacylglycerol was decreased by 15-20%, and 30% respectively with these non-β-oxidizable fatty acid derivatives. The CoA ester of TTA inhibited the esterification of 1,2-diacylglycerol in rat liver microsomes. Both eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) activated GR-PPARα. EPA increased the oxidation of[1-¹⁴C]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 diacylglycerol 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 [1-¹⁴C]oleic acid into secreted triacylglycerol was decreased by 20% in the presence of EPA. In conclusion, a decreased availability of fatty acids for triacylglycerol synthesis by increased mitochondrial β-oxidation and decreased triacylglycerol formation caused by inhibition of diacylglycerol acyltransferase might explain the hypolipidaemic effect of TTA and EPA.