Control of 3-hydroxy-3-methylglutaryl-CoA reductase activity in cultured human fibroblasts by very low density lipoproteins of subjects with hypertriglyceridemia.
Control of 3-hydroxy-3-methylglutaryl-CoA reductase activity in cultured human fibroblasts by very low density lipoproteins of subjects with hypertriglyceridemia.
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通过高甘油三酯血症受试者的极低密度脂蛋白控制培养的人成纤维细胞中的 3-羟基-3-甲基戊二酰辅酶 A 还原酶活性。
DOI：
10.1172/jci108942
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发表时间：
1978
期刊：
影响因子：
--
通讯作者：
L. C. Smith
中科院分区：
文献类型：
--
作者：
S. Gianturco;A. Gotto;R. Jackson;J. Patsch;H. Sybers;O. Taunton;D. Yeshurun;L. C. Smith
测试了来自正常血脂血浆的极低密度脂蛋白 (VLDL) 和低密度脂蛋白 (LDL)，以及来自 III 型高脂蛋白血症血浆的 VLDL、中密度脂蛋白 (IDL) 和 LDL 抑制正常受试者和 III 型患者培养的人成纤维细胞中 3-羟基-3-甲基戊二酰辅酶 A (HMG-CoA) 还原酶活性的能力。 III 型高脂蛋白血症患者的成纤维细胞中胆固醇合成的调节似乎是正常的。根据蛋白质含量，通过角头超速离心 (d < 1.006) 或通过 BioGel A-5m 凝胶过滤分离的正常受试者中的 VLDL 在抑制 HMG-CoA 还原酶活性方面的效果比 LDL 低约 5 倍，这与之前对正常成纤维细胞的报道一致。通过两种方法分离的正常VLDL的区域离心显示VLDL含有IDL。来自角头转子的正常 VLDL，通过区域方法折射，几乎没有抑制正常或 III 型成纤维细胞中 HMG-CoA 还原酶活性的能力。 VLDL、IDL 和 LDL 通过区域超速离心从 III 型血浆中分离，在 0.2-0.5 微克蛋白质/ml 时产生半最大抑制，与正常 LDL 引起的抑制没有区别。 III 型 VLDL 不会抑制突变 LDL 受体阴性成纤维细胞中的 HMG-CoA 还原酶。从一名 IV 型和一名 V 型患者获得的区域分离的 VLDL 分别在 5 和 0.5 微克蛋白质/ml 下产生半最大抑制。带状分离的正常 VLDL 和 III 型 VLDL 的分子直径和脱辅基蛋白组成相似；成分上的主要区别在于，III 型 VLDL 比正常 VLDL 含有更多的胆固醇酯和更少的甘油三酯。 IV型和V型VLDL的成分和直径与正常VLDL相似。这些发现表明，III型高脂蛋白血症的基本缺陷与家族性高胆固醇血症中发现的细胞缺陷有本质上的不同，因为HMG-CoA还原酶活性的调节在III型成纤维细胞中是正常的。高甘油三酯血症的代谢缺陷与富含甘油三酯的脂蛋白有关，该脂蛋白不含其他脂蛋白，与培养的成纤维细胞相互作用以调节HMG-CoA还原酶活性的能力增强。这些研究表明，在高甘油三酯血症中，存在一种 VLDL 直接细胞分解代谢的机制，该机制对于正常 VLDL 不起作用。
Very low density lipoproteins (VLDL) and low density lipoproteins (LDL) from human normolipemic plasma, and the VLDL, the intermediate density lipoprotein (IDL), and LDL from patients with Type III hyperlipoproteinemic plasma were tested for their abilities to suppress the activity of 3-hydroxy-3-methylglutaryl-Coenzyme A (HMG-CoA) reductase in cultured human fibroblasts from normal subjects and a Type III patient. Regulation of cholesterol synthesis in the fibroblasts of a patient with Type III hyperlipoproteinemia appears to be normal. VLDL from normal subjects, isolated by angle head ultracentrifugation (d < 1.006) or by gel filtration on BioGel A-5m, were about 5 times less effective than LDL in suppressing HMG-CoA reductase activity, based on protein content, in agreement with previous reports with normal fibroblasts. Zonal centrifugation of normal VLDL isolated by both methods showed that the VLDL contained IDL. Normal VLDL from the angle head rotor, refractionated by the zonal method, had little, if any, ability to suppress the HMG-CoA reductase activity in either normal or Type III fibroblasts. VLDL, IDL, and LDL fractionated by zonal ultracentrifugation from Type III plasma gave half-maximum inhibition at 0.2-0.5 mug of protein/ml, indistinguishable from the suppression caused by normal LDL. Type III VLDL did not suppress HMG-CoA reductase in mutant LDL receptor-negative fibroblasts. Zonally isolated VLDL obtained from one Type IV and one Type V patient gave half-maximal suppression at 5 and 0.5 mug of protein/ml, respectively. Molecular diameters and apoprotein compositions of the zonally isolated normal and Type III VLDL were similar; the major difference in composition was that Type III VLDL contained more cholesteryl esters and less triglyceride than did normal VLDL. The compositions and diameters of the Type IV and Type V VLDL were similar to normal VLDL. These findings show that the basic defect in Type III hyperlipoproteinemia is qualitatively different from the cellular defect found in familial hypercholesterolemia, since the regulation of HMG-CoA reductase activity is normal in Type III fibroblasts. The metabolic defect in hypertriglyceridemia is related to the triglyceriderich lipoproteins which, free of other lipoproteins, have an enhanced ability to interact with cultured fibroblasts to regulate HMG-CoA reductase activity. These studies suggest that, in hypertriglyceridemia, there is a mechanism for direct cellular catabolism of VLDL which is not functional for normal VLDL.