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-substituted non-beta-oxidizable fatty acid analogue 1,10 bis(carboxymethylthio)decane, also known as 3-thiadicarboxylic acid, was studied in normolipidemic rats. Treatment with 3-thiadicarboxylic acid markedly decreased plasma levels of free fatty acids, triglycerides, and cholesterol. This was accompanied by a corresponding reduction in very low density lipoprotein (VLDL)-triglyceride and low density lipoprotein (LDL)-cholesterol levels (by 46% and 42%, respectively), whereas the decrease in high density lipoprotein (HDL)-cholesterol levels was less pronounced (16%). However, the composition of the various plasma lipoprotein fractions was essentially unchanged. Fatty acid oxidation in both mitochondria and peroxisomes was stimulated in parallel; the activities of ATP:citrate lyase and fatty acid synthase, two key enzymes in fatty acid synthesis, were inhibited. Hepatic triglyceride biosynthesis was retarded, 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 were somewhat higher (18%) in treated animals, suggesting a slight increase in the clearance potential of triglyceride-rich lipoproteins. The cholesterol-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 acyltransferase (25%) activities. The present data suggest that the hypotriglyceridemic and hypocholesterolemic properties of sulfur-substituted fatty acid analogues are primarily due to effects on triglyceride and cholesterol synthesis.
Skorve
J
J
Laboratory of Clinical Biochemistry, University of Bergen, Haukeland Sykehus, Norway.
al-Shurbaji
A
A
Asiedu
D
D
Björkhem
I
I
Berglund
L
L
Berge
R K
RK
D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis / Q000097:blood*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000187:drug effects*; D003998:Dicarboxylic Acids / Q000494:pharmacology*; D004951:Esterification; D005227:Fatty Acids / Q000097:blood; D006903:Hydroxymethylglutaryl CoA Reductases / Q000187:drug effects*; D008055:Lipids / Q000096:biosynthesis / Q000097:blood*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D002785:Sterol O-Acyltransferase / Q000187:drug effects*; D013440:Sulfides / Q000494:pharmacology*; D014280:Triglycerides / Q000096:biosynthesis / Q000378:metabolism
D003998:Dicarboxylic Acids; D005227:Fatty Acids; D008055:Lipids; D013440:Sulfides; D014280:Triglycerides; C062079:1,10-bis(carboxymethylthiodecane); D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D002790:Cholesterol 7-alpha-Hydroxylase; D002785:Sterol O-Acyltransferase