On the mechanism of the hypolipidemic effect of sulfur-substituted hexadecanedioic acid (3-thiadicarboxylic acid) in normolipidemic rats

J. Skorve, A. Al-Shurbaji, D. Asiedu, I. Bjorkhem, Lars Berglund, R. K. Berge

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Abstract

The mechanism behind the hypolipidemic effect of the sulfur-substituted non-β-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 α- 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.

Original languageEnglish (US)
Pages (from-to)1177-1185
Number of pages9
JournalJournal of Lipid Research
Volume34
Issue number7
StatePublished - 1993
Externally publishedYes

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Keywords

  • ACAT
  • cholesterol 7 α-hydroxylase
  • hepatic lipase
  • HMG-CoA reductase
  • hypolipidemic drug
  • lipogenic enzymes
  • lipoprotein composition
  • lipoprotein lipase
  • plasma lipids
  • triglyceride and cholesterol synthesis

ASJC Scopus subject areas

  • Endocrinology

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