ENHANCED HEPATIC FATTY-ACID OXIDATION AND UP-REGULATED CARNITINE PALMITOYLTRANSFERASE-II GENE-EXPRESSION BY METHYL 3-THIAOCTADECA-6,9,12,15-TETRAENOATE IN RATS

This study reports the effects of a novel polyunsaturated 3-thia fatty acid, methyl 3-thiaoctadeca-6,9,12,15-tetraenoate on serum lipids and key enzymes in hepatic fatty acid metabolism compared to a saturated 3-thia fatty acid, tetradecylthioacetic acid. Palmitic acid treated ra ts served as controls. Fatty acids were administered by gavage in dail y doses of 150 mg/kg body weight for 10 days. The aim of the present s tudy was: (a) To investigate the effect of a polyunsaturated 3-thia fa tty acid ester, methyl 3-thiaoctadeca-6,9,12,15-tetraenoate on plasma lipids in normolipidemic rats; (b) to verify whether the lipid-lowerin g effect could be consistent with enhanced fatty acid oxidation; and ( c) to study whether decreased activity of esterifying enzymes and dive rsion to phospholipid synthesis is a concerted mechanism in limiting t he availability of free fatty acid as a substrate for hepatic triglyce ride formation. Repeated administration of the polyunsaturated 3-thia fatty acid ester for 10 days resulted in a reduction of plasma triglyc erides (40%), cholesterol (33%) and phospholipids (20%) compared to co ntrols. Administration of polyunsaturated and saturated 3-thia fatty a cids (daily doses of 150 mg/kg body weight) reduced levels of lipids t o a similar extent and followed about the same time-course. Both mitoc hondrial and peroxisomal fatty acid oxidation increased (1,4-fold- and 4.2-fold, respectively) and significantly increased activities of car nitine palmitoyltransferase (CPT) (1.6-fold), 2,4-dienoyl-CoA reductas e (1.2-fold) and fatty acyl-CoA oxidase (3.0-fold) were observed in po lyunsaturated 3-thia fatty acid treated animals. This was accompanied by increased CPT-II mRNA (1.7-fold), 2,4-dienoyl-CoA reductase mRNA (2 .9-fold) and fatty acyl-CoA oxidase mRNA (1.7-fold). Compared to contr ols, the hepatic triglyceride biosynthesis was retarded as indicated b y a decrease in liver triglyceride content (40%). The activities of gl ycerophosphate acyltransferase, acyl-CoA: 1,2-diacylglycerol acyltrans ferase and CTP: phosphocholine cytidylyltransferase were increased. Th e cholesterol lowering effect was accompanied by a reduction in HMG-Co A reductase activity (80%) and acyl-CoA: cholesterol acyltransferase a ctivity (33%). In hepatocytes treated with methyl 3-thiaoctadeca-6,9,1 2,15-tetraenoate, fatty acid oxidation was increased 1.8-fold compared to controls. The results suggest that treatment with methyl 3-thiaoct adeca-6,9,12,15-tetraenoate reduces plasma triglycerides by a decrease in the availability of fatty acid substrate for triglyceride biosynth esis via enhanced fatty acid oxidation, most likely attributed to the mitochondrial fatty acid oxidation. It is hypothesized that decreased phosphatidate phosphohydrolase activity may be an additive mechanism w hich contribute whereby 3-thia fatty acids reduce triglyceride formati on in the liver. The cholesterol-lowering effect of the polyunsaturate d 3-thia fatty acid ester may be due to changes in cholesterol/cholest erol ester synthesis as 60% of this acid was observed in the hepatic c holesterol ester fraction. (C) 1997 Elsevier Science B. V.