Skorve J, al-Shurbaji A, Asiedu D, Björkhem I, Berglund L, Berge R K
Laboratory of Clinical Biochemistry, University of Bergen, Haukeland Sykehus, Norway.
J Lipid Res. 1993 Jul;34(7):1177-85.
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.
在血脂正常的大鼠中研究了硫取代的非β氧化脂肪酸类似物1,10-双（羧甲基硫基）癸烷（也称为3-硫代二羧酸）降血脂作用的机制。用3-硫代二羧酸处理可显著降低血浆游离脂肪酸、甘油三酯和胆固醇水平。这伴随着极低密度脂蛋白（VLDL）-甘油三酯和低密度脂蛋白（LDL）-胆固醇水平相应降低（分别降低46%和42%），而高密度脂蛋白（HDL）-胆固醇水平的降低则不太明显（16%）。然而，各种血浆脂蛋白组分的组成基本未变。线粒体和过氧化物酶体中的脂肪酸氧化同时受到刺激；脂肪酸合成中的两个关键酶ATP：柠檬酸裂解酶和脂肪酸合酶的活性受到抑制。肝脏甘油三酯生物合成受到抑制，表现为肝脏甘油三酯含量降低以及肝脏VLDL-甘油三酯分泌减少30%。这伴随着磷脂酸磷酸水解酶50%的抑制。处理动物的血浆脂蛋白脂肪酶和肝脏脂肪酶活性略有升高（18%），表明富含甘油三酯的脂蛋白清除潜力略有增加。降胆固醇作用伴随着HMG-CoA还原酶活性显著降低（75%）以及胆固醇7α-羟化酶（52%）和酰基辅酶A：胆固醇酰基转移酶（25%）活性受到不太明显的抑制。目前的数据表明，硫取代脂肪酸类似物的降甘油三酯和降胆固醇特性主要归因于对甘油三酯和胆固醇合成的影响。
