Effect of 3‐Thiadicarboxylic Acid on Lipid Metabolism in Experimental Nephrosis
作者:
Ayman AL-Shurbaji,
Jon Skorve,
Rolf Berge,
Mats Rudling,
Ingemar Bjorkhem,
Lars Berglund,
期刊:
Arteriosclerosis and Thrombosis: A Journal of Vascular Biology
(OVID Available online 1993)
卷期:
Volume 13,
issue 11
页码: 1580-1586
ISSN:1049-8834
年代: 1993
出版商: OVID
关键词: triacylglycerol;3-hydroxy-3-methylglutaryl-coenzyme A reductase;hypolipidemic drugs;lipoprotein synthesis;cholesterol;β-oxidation
数据来源: OVID
摘要:
The effect of the sulfur-substituted fatty acid analogue 1,10 6i?(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 /3-oxidation of fatty acids ninefold and the mitochondrial β-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-lowdensity lipoprotein synthesis and secretion is strongly influenced by the availability of the fatty acid substrate under the same hyperlipidemic conditions.
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