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.
Skorve
J
J
Laboratory of Clinical Biochemistry, University of Bergen, Haukeland Sykehus, Norway.
Berge
R K
RK
D000818:Animals; D002784:Cholesterol / Q000097:blood* / Q000378:metabolism; D003998:Dicarboxylic Acids / Q000494:pharmacology*; D004040:Dietary Carbohydrates / Q000008:administration & dosage*; D004075:Diglycerides / Q000378:metabolism; D015536:Down-Regulation; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D025782:Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent; D008099:Liver / Q000378:metabolism*; D008297:Male; D009097:Multienzyme Complexes / Q000378:metabolism; D007652:Oxo-Acid-Lyases / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D002785:Sterol O-Acyltransferase / Q000378:metabolism*; D013440:Sulfides / Q000494:pharmacology*; D014280:Triglycerides / Q000378:metabolism
C011439:1,2-diacylglycerol; D003998:Dicarboxylic Acids; D004040:Dietary Carbohydrates; D004075:Diglycerides; D009097:Multienzyme Complexes; D010743:Phospholipids; D013440:Sulfides; D014280:Triglycerides; C062079:1,10-bis(carboxymethylthiodecane); C062078:1-(carboxymethylthio)tetradecane; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D025782:Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent; D002785:Sterol O-Acyltransferase; D007652:Oxo-Acid-Lyases; C019909:citrate (pro-3S)-lyase