title: Effect of 3-thiadicarboxylic acid on lipid metabolism in experimental nephrosis.
abstract: The effect of the sulfur-substituted fatty acid analogue 1,10 bis(carboxymethylthio)decane, also known as 3-thiadicarboxylic acid, on puromycin aminonucleoside-induced nephrotic hyperlipidemia was studied in rats. Treatment with 3-thiadicarboxylic acid (250 mg/kg) for 5 days reduced plasma levels of triglycerides from 5.8 to 2.7 mmol/L and cholesterol from 11.0 to 7.7 mmol/L. This was accounted for by decreases in very-low-density lipoprotein triglycerides, very-low-density lipoprotein cholesterol, and low-density lipoprotein cholesterol, without any major changes in the composition of plasma lipoproteins. The activities of two enzymes involved in fatty acid synthesis (ATP:citrate lyase and fatty acid synthetase) were inhibited by 3-thiadicarboxylic acid treatment, whereas acetyl-coenzyme A carboxylase activity was unchanged. In contrast, treatment with the sulfur-substituted fatty acid analogue induced the peroxisomal beta-oxidation of fatty acids ninefold and the mitochondrial beta-oxidation by 54% to 73%, depending on the substrate used. This was accompanied by a 26% reduction in hepatic triglyceride secretion rate. The hepatic phosphatidate phosphohydrolase activity was unchanged. 3-Thiadicarboxylic acid treatment suppressed the activity of the rate-limiting enzyme in cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl-coenzyme A reductase, by 58%, whereas hepatic LDL receptor expression was unaltered. The activities of lipoprotein lipase and hepatic lipase were unchanged by treatment. These results demonstrated that treatment with 3-thiadicarboxylic acid ameliorates hyperlipidemia in experimental nephrosis primarily by decreasing the overproduction of very-low-density lipoprotein present. The data also indicate that hepatic very-low-density lipoprotein synthesis and secretion is strongly influenced by the availability of the fatty acid substrate under the same hyperlipidemic conditions.
authors.affiliation: Department of Clinical Chemistry, Karolinska Institutet, Huddinge University Hospital, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: al-Shurbaji
authors.forename: J
authors.initials: J
authors.lastname: Skorve
authors.forename: R K
authors.initials: RK
authors.lastname: Berge
authors.forename: M
authors.initials: M
authors.lastname: Rudling
authors.forename: I
authors.initials: I
authors.lastname: Björkhem
authors.forename: L
authors.initials: L
authors.lastname: Berglund
mesh_terms: D001275:ATP Citrate (pro-S)-Lyase / Q000037:antagonists & inhibitors; D000818:Animals; D002784:Cholesterol / Q000097:blood; D002790:Cholesterol 7-alpha-Hydroxylase / Q000037:antagonists & inhibitors; D008078:Cholesterol, LDL / Q000097:blood; D015243:Cholesterol, VLDL / Q000097:blood; D003998:Dicarboxylic Acids / Q000494:pharmacology*; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors; D005230:Fatty Acids, Nonesterified / Q000097:blood; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids / Q000097:blood*; D008079:Lipoproteins, VLDL / Q000097:blood; D008297:Male; D009401:Nephrosis / Q000097:blood* / Q000139:chemically induced; D011692:Puromycin Aminonucleoside; D051381:Rats; D017207:Rats, Sprague-Dawley; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors; D013440:Sulfides / Q000494:pharmacology*; D014280:Triglycerides / Q000097:blood
chemical_list: D008078:Cholesterol, LDL; D015243:Cholesterol, VLDL; D003998:Dicarboxylic Acids; D005230:Fatty Acids, Nonesterified; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D008079:Lipoproteins, VLDL; D013440:Sulfides; D014280:Triglycerides; C030106:very low density lipoprotein triglyceride; C062079:1,10-bis(carboxymethylthiodecane); D011692:Puromycin Aminonucleoside; D002784:Cholesterol; D002790:Cholesterol 7-alpha-Hydroxylase; D002785:Sterol O-Acyltransferase; D064429:Fatty Acid Synthases; D001275:ATP Citrate (pro-S)-Lyase