title: 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.
abstract: Hypolipidaemic fatty acid derivatives and polyunsaturated fatty acids decrease concentrations of plasma triacylglycerol by mechanisms that are not fully understood. Because poor susceptibility to beta- and/or omega-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 alpha (PPARalpha), fatty acid oxidation and triacylglycerol synthesis were examined. We have compared the effects of differentially beta-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-beta-oxidizable fatty acid derivatives, were potent activators of a glucocorticoid receptor (GR)-PPARalpha chimaera. This activation was paradoxically reflected in an substantially increased oxidation of [1-(14)C]palmitic acid and/or oleic acid. The incorporation of [1-(14)C]palmitic acid and/or oleic acid into cell-associated and secreted triacylglycerol was decreased by 15-20% and 30% respectively with these non-beta-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-PPARalpha. EPA increased the oxidation of [1-(14)C]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-(14)C]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 beta-oxidation and decreased triacylglycerol formation caused by inhibition of diacylglycerol acyltransferase might explain the hypolipidaemic effect of TTA and EPA.
authors.affiliation: Department of Clinical Biochemistry, University of Bergen, Haukeland Hospital, N-5021 Bergen, Norway. rolf.berge@ikb.uib.no
authors.forename: R K
authors.initials: RK
authors.lastname: Berge
authors.forename: L
authors.initials: L
authors.lastname: Madsen
authors.forename: H
authors.initials: H
authors.lastname: Vaagenes
authors.forename: K J
authors.initials: KJ
authors.lastname: Tronstad
authors.forename: M
authors.initials: M
authors.lastname: Göttlicher
authors.forename: A C
authors.initials: AC
authors.lastname: Rustan
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors*; D000818:Animals; D051048:Diacylglycerol O-Acyltransferase; D004281:Docosahexaenoic Acids / Q000737:chemistry / Q000494:pharmacology*; D015118:Eicosapentaenoic Acid / Q000737:chemistry / Q000494:pharmacology*; D005227:Fatty Acids / Q000378:metabolism*; D000960:Hypolipidemic Agents / Q000737:chemistry / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists; D011993:Recombinant Fusion Proteins / Q000819:agonists; D014157:Transcription Factors / Q000819:agonists; D014280:Triglycerides / Q000096:biosynthesis*
chemical_list: D005227:Fatty Acids; D000960:Hypolipidemic Agents; D018160:Receptors, Cytoplasmic and Nuclear; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D014280:Triglycerides; D004281:Docosahexaenoic Acids; D015118:Eicosapentaenoic Acid; D000217:Acyltransferases; D051048:Diacylglycerol O-Acyltransferase