LOCALIZATION OF LOW-DENSITY LIPOPROTEIN RECEPTORS ON PLASMA-MEMBRANE OF NORMAL HUMAN FIBROBLASTS AND THEIR ABSENCE IN CELLS FROM A FAMILIAL HYPERCHOLESTEROLEMIA HOMOZYGOTE
LOCALIZATION OF LOW-DENSITY LIPOPROTEIN RECEPTORS ON PLASMA-MEMBRANE OF NORMAL HUMAN FIBROBLASTS AND THEIR ABSENCE IN CELLS FROM A FAMILIAL HYPERCHOLESTEROLEMIA HOMOZYGOTE
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DOI：
10.1073/pnas.73.7.2434
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发表时间：
1976-01-01
影响因子：
11.1
通讯作者：
BROWN, MS
中科院分区：
文献类型：
--
作者：
ANDERSON, RGW;GOLDSTEIN, JL;BROWN, MS
单层正常人成纤维细胞被观察到结合铁蛋白标记的低密度脂蛋白（LDL-铁蛋白）在细胞表面膜上的特定受体位点。当成纤维细胞与LDL-铁蛋白在4 ℃温育时，超过70%的表面结合的铁蛋白核心通过EM定位于质膜的短片段，其中膜看起来是凹进的并且在其两侧上被绒毛材料涂覆。这些膜片段对应于先前在其他细胞类型中描述的包被区域。在正常细胞中，平均55个LDL-铁蛋白颗粒与每mm质膜结合。在存在15倍过量的天然LDL的情况下，结合的铁蛋白核心的数量减少了75%，这表明LDL-铁蛋白与特异性LDL受体位点结合。虽然来自患有纯合子形式的家族性高胆固醇血症的患者的成纤维细胞与正常细胞一样含有相同数量的缩进的、包被的膜区域/mm的细胞表面，但是在这些突变细胞中没有观察到LDL-铁蛋白与细胞膜结合。目前的超微结构数据与以前的生化和遗传证据一致，表明LDL通过与特定的细胞表面受体相互作用对成纤维细胞中的细胞胆固醇代谢发挥其调节作用，并且该受体在纯合子家族性高胆固醇血症成纤维细胞中是有缺陷的。LDL受体可能定位于质膜的锯齿状包被区域，似乎参与蛋白质的吸附性内吞作用。
Monolayers of normal human fibroblasts were observed to bind ferritin-labeled low density lipoprotein (LDL-ferritin) at specific receptor sites on the cell surface membrane. When fibroblasts were incubated with LDL-ferritin at 4.degree., more than 70% of the surface-bound ferritin cores were localized by EM to short segments of the plasma membrane where the membrane appeared indented and coated on both of its sides by a fuzzy material. These membrane segments corresponded to coated regions previously described in other cell types. An average of 55 LDL-ferritin particles were bound to each mm of plasma membrane in normal cells. In the presence of a 15-fold excess of native LDL, the number of bound ferritin cores was reduced by 75%, suggesting that the LDL-ferritin was binding to specific LDL receptor sites. Although fibroblasts from a patient with the homozygous form of familial hypercholesterolemia contained the same number of indented, coated membrane regions/mm of cell surface as did normal cells, no LDL-ferritin was observed to bind to the cell membrane in these mutant cells. The present ultrastructural data are consistent with previous biochemical and genetic evidence indicating that LDL exerts its regulatory action on cellular cholesterol metabolism in fibroblasts through an interaction with a specific cell surface receptor and that this receptor is defective in homozygous familial hypercholesterole mia fibroblasts. The LDL receptor may be localized to indented, coated regions of the plasma membrane that appear to participate in the adsorptive endocytosis of proteins.