RELEASE OF LOW-DENSITY LIPOPROTEIN FROM ITS CELL-SURFACE RECEPTOR BY SULFATED GLYCOSAMINOGLYCANS
RELEASE OF LOW-DENSITY LIPOPROTEIN FROM ITS CELL-SURFACE RECEPTOR BY SULFATED GLYCOSAMINOGLYCANS
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DOI：
10.1016/0092-8674(76)90258-0
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发表时间：
1976-01-01
期刊：
影响因子：
64.5
通讯作者：
BROWN, MS
中科院分区：
文献类型：
--
作者：
GOLDSTEIN, JL;BASU, SK;BROWN, MS
硫酸化糖胺聚糖肝素可从正常人成纤维细胞表面的受体部位释放~（125）I-LDL。通过测定肝素释放的125 I-LDL的量，可以解析37 ℃时细胞对125 I-LDL的总摄取。C分为2个组分：脂蛋白与表面受体的初始快速、高亲和力结合，125 I-LDL可通过肝素从表面受体释放，以及归因于受体结合脂蛋白的内吞作用的较慢过程，这使其对肝素释放具有抗性。在4.5度。C时肝素可释放的125 I-LDL的量与37 ℃时相似。但在较低温度下脂蛋白不发生变性。细胞表面LDL受体的生理学重要性通过以下发现得到强调：来自患有纯合家族性高胆固醇血症的受试者的突变成纤维细胞缺乏在37 ℃摄取125 I-LDL的能力。C，在4 ° C下均未显示125 I-LDL的细胞表面结合（通过肝素释放测量）。C或37 ° C。C.尽管肝素从其结合位点释放125 I-LDL，但它不从其表面受体释放3 H-伴刀豆球蛋白A，相反，α-LDL从其表面受体释放3 H-伴刀豆球蛋白A。甲基-D-吡喃甘露糖苷释放3 H-伴刀豆球蛋白A，不释放表面结合的125 I-LDL。当与LDL同时加入培养基中时，肝素阻止LDL与其受体结合，从而阻止LDL介导的3-羟基-3-甲基戊二酰辅酶A还原酶活性抑制。成纤维细胞对LDL的摄取被认为是人体细胞中受体介导的大分子吸附性内吞作用的模型。
The sulfated glycosaminoglycan, heparin, was found to release 125I-labeled low density lipoprotein (125I-LDL) from its receptor site on the surface of normal human fibroblasts. Measurement of the amount of 125I-LDL released by heparin permitted the resolution of the total cellular uptake of 125I-LDL at 37.degree. C into 2 components: an initial rapid, high affinity binding of the lipoprotein to the surface receptor, from which the 125I-LDL could be released by heparin, and a slower process attributable to an endocytosis of the receptor-bound lipoprotein, which rendered it resistant to heparin release. At 4.degree. C the amount of heparin-releasable 125I-LDL was similar to that at 37.degree. C, but interiorization of the lipoprotein did not occur at the lower temperature. The physiologic importance of the cell surface LDL receptor was emphasized by the finding that mutant fibroblasts from a subject with homozygous familial hypercholesterolemia, which lack the ability to take up 125I-LDL at 37.degree. C, did not show cell surface binding of 125I-LDL, as measured by heparin release, at either 4.degree. C or 37.degree. C. Although heparin released 125I-LDL from its binding site, it did not release 3H-concanavalin A from its surface receptor, and conversely, .alpha.-methyl-D-mannopyranoside, which released 3H-concanavalin A, did not release surface-bound 125I-LDL. When added to the culture medium simultaneously with LDL, heparin prevented the binding of LDL to its receptor and hence prevented the LDL-mediated suppression of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. The uptake of LDL by fibroblasts is proposed as a model of receptor-mediated adsorptive endocytosis of macromolecules in human cells.