ON THE MECHANISM OF THE HYPOLIPIDEMIC EFFECT OF SULFUR-SUBSTITUTED HEXADECANEDIOIC ACID (3-THIADICARBOXYLIC ACID) IN NORMOLIPIDEMIC RATS

The mechanism behind the hypolipidemic effect of the sulfur-substitute d non-beta-oxidizable fatty acid analogue 1,10 bis(carboxymethylthio)d ecane, also known as 3-thiadicarboxylic acid, was studied in normolipi demic rats. Treatment with 3-thiadicarboxylic acid markedly decreased plasma levels of free fatty acids, triglycerides, and cholesterol. Thi s was accompanied by a corresponding reduction in very low density lip oprotein (VLDL)-triglyceride and low density lipoprotein (LDL)-cholest erol levels (by 46% and 42%, respectively), whereas the decrease in hi gh density lipoprotein (HDL)-cholesterol levels was less pronounced (1 6%). However, the composition of the various plasma lipoprotein fracti ons was essentially unchanged. Fatty acid oxidation in both mitochondr ia and peroxisomes was stimulated in parallel; the activities of ATP:c itrate lyase and fatty acid synthase, two key enzymes in fatty acid sy nthesis, were inhibited. Hepatic triglyceride biosynthesis was retarde d, as indicated by a decrease in the liver triglyceride content along with a 30% reduction of hepatic VLDL-triglyceride secretion. This was accompanied by a 50% inhibition of phosphatidate phosphohydrolase. The activities of plasma lipoprotein lipase as well as hepatic lipase wer e somewhat higher (18%) in treated animals, suggesting a slight increa se in the clearance potential of triglyceride-rich lipoproteins. The c holesterol-lowering effect was accompanied by a considerable reduction (75%) in HMG-CoA reductase activity and a less pronounced inhibition of cholesterol 7 alpha-hydroxylase (52%), and acyl-CoA:cholesterol acy ltransferase (25%) activities. The present data suggest that the hypot riglyceridemic and hypocholesterolemic properties of sulfur-substitute d fatty acid analogues are primarily due to effects on triglyceride an d cholesterol synthesis.