The hypocholesterolemic effect of sulfur-substituted fatty acid analogues in rats fed a high carbohydrate diet.

Sulfur-substituted fatty acid analogues have been administered to rats fed a high carbohydrate diet, and the effect on plasma and hepatic lipid metabolism was investigated. Two of the analogues studied, 3-thiadicarboxylic acid and tetradecylthioacetic acid, reduced the plasma cholesterol level significantly, whereas the effect on plasma triacylglycerol level was only marginal. 3-Thiadicarboxylic acid was the most potent, decreasing the cholesterol level faster and at a lower dose than tetradecylthioacetic acid. The relative effects on plasma cholesterol and triacylglycerol levels were different from what have been observed in rats fed a conventional pellet diet. Tetradecylthiopropionic acid had no hypocholesterolemic effect. The activities of three lipogenic enzymes: ATP-citrate lyase, acetyl-CoA carboxylase and fatty acid synthase was measured. The two hypocholesterolemic analogues reduced the activities of these enzymes in a coordinated manner. The enzyme activities was found to correlate with the the plasma cholesterol level, indicating a coordinated regulation of these enzymes and cholesterol synthesis or secretion. The effect on two enzymes involved in cholesterol metabolism was also studied. The activity of acyl-CoA:cholesterol acyltransferase (ACAT) was reduced by the two hypocholesterolemic analogues, in contrast to the rate-limiting enzyme in cholesterol biosynthesis, HMG-CoA reductase, which tended to increase. The cholesterol lowering effect of 3-thiadicarboxylic acid and tetradecylthioacetic acid can probably be ascribed to diminished cholesterol synthesis due to a reduced availability of acetyl-CoA. A reduction in the esterification of hepatic cholesterol may be a contributing factor.