al-Shurbaji A, Skorve J, Berge R K, Rudling M, Björkhem I, Berglund L
Department of Clinical Chemistry, Karolinska Institutet, Huddinge University Hospital, Sweden.
Arterioscler Thromb. 1993 Nov;13(11):1580-6. doi: 10.1161/01.atv.13.11.1580.
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.
研究了硫取代脂肪酸类似物1,10 - 双（羧甲基硫基）癸烷（也称为3 - 硫代二羧酸）对嘌呤霉素氨基核苷诱导的肾病性高脂血症大鼠的影响。用3 - 硫代二羧酸（250 mg/kg）治疗5天，可使血浆甘油三酯水平从5.8 mmol/L降至2.7 mmol/L，胆固醇水平从11.0 mmol/L降至7.7 mmol/L。这是由于极低密度脂蛋白甘油三酯、极低密度脂蛋白胆固醇和低密度脂蛋白胆固醇的降低所致，血浆脂蛋白组成无任何重大变化。3 - 硫代二羧酸处理可抑制参与脂肪酸合成的两种酶（ATP：柠檬酸裂解酶和脂肪酸合成酶）的活性，而乙酰辅酶A羧化酶活性未改变。相比之下，硫取代脂肪酸类似物处理可使脂肪酸的过氧化物酶体β - 氧化增加9倍，线粒体β - 氧化增加54%至73%，具体取决于所用底物。这伴随着肝脏甘油三酯分泌率降低26%。肝脏磷脂酸磷酸水解酶活性未改变。3 - 硫代二羧酸处理可使胆固醇生物合成中的限速酶3 - 羟基 - 3 - 甲基戊二酰辅酶A还原酶的活性降低58%，而肝脏低密度脂蛋白受体表达未改变。脂蛋白脂肪酶和肝脏脂肪酶的活性不受处理影响。这些结果表明，3 - 硫代二羧酸治疗可通过减少存在的极低密度脂蛋白的过量产生来改善实验性肾病中的高脂血症。数据还表明，在相同的高脂血症条件下，肝脏极低密度脂蛋白的合成和分泌受到脂肪酸底物可用性的强烈影响。
