THE HYPOCHOLESTEROLEMIC EFFECT OF SULFUR-SUBSTITUTED FATTY-ACID ANALOGS 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 li pid metabolism was investigated. Two of the analogues studied, 3-thiad icarboxylic acid and tetradecylthioacetic acid, reduced the plasma cho lesterol level significantly, whereas the effect on plasma triacyiglyc erol level was only marginal. 3-Thiadicarboxylic acid was the most pot ent, 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 e nzymes: ATP-citrate lyase, acetyl-CoA carboxylase and fatty acid synth ase was measured. The two hypocholesterolemic analogues reduced the ac tivities of these enzymes in a coordinated manner. The enzyme activiti es was found to correlate with the the plasma cholesterol level, indic ating a coordinated regulation of these enzymes and cholesterol synthe sis or secretion. The effect on two enzymes involved in cholesterol me tabolism was also studied. The activity of acyl-CoA:cholesterol acyltr ansferase (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 pr obably be ascribed to diminished cholesterol synthesis due to a reduce d availability of acetyl-CoA. A reduction in the esterification of hep atic cholesterol may be a contributing factor.