BINDING-SITE ON MACROPHAGES THAT MEDIATES UPTAKE AND DEGRADATION OF ACETYLATED LOW-DENSITY LIPOPROTEIN, PRODUCING MASSIVE CHOLESTEROL DEPOSITION
BINDING-SITE ON MACROPHAGES THAT MEDIATES UPTAKE AND DEGRADATION OF ACETYLATED LOW-DENSITY LIPOPROTEIN, PRODUCING MASSIVE CHOLESTEROL DEPOSITION
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DOI：
10.1073/pnas.76.1.333
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发表时间：
1979-01-01
影响因子：
11.1
通讯作者：
BROWN, MS
中科院分区：
文献类型：
--
作者：
GOLDSTEIN, JL;HO, YK;BROWN, MS
小鼠腹腔巨噬细胞在体外摄取和降解乙酰化125i标记的低密度脂蛋白（125I-acetyl-LDL）的速度比摄取和降解125I-LDL的速度高20倍。125i -乙酰-LDL的摄取及其随后在溶酶体中的降解可归因于一个高亲和力、胰蛋白酶敏感的表面结合位点，该位点识别乙酰-LDL，但不识别天然LDL。当125i -乙酰- ldl以4度结合到这个位点时。C，随后将巨噬细胞加热至37度。C， 75%的细胞结合放射性在1小时内降解为单[125I]碘酪氨酸。巨噬细胞结合位点还识别马来酰化LDL，马来酰化白蛋白和2硫酸化多糖（岩藻苷和硫酸葡聚糖），表明负电荷在结合反应中很重要。在大鼠腹膜巨噬细胞、豚鼠库普弗细胞和培养的人单核细胞中发现了类似的结合位点，但在人淋巴细胞或成纤维细胞、小鼠成纤维细胞L细胞或Y-1肾上腺腺瘤细胞或中国仓鼠卵巢细胞中没有发现。通过该结合位点摄取和降解乙酰- ldl可刺激胆固醇酯化100倍，并使小鼠腹膜巨噬细胞中胆固醇含量增加38倍。尽管这种巨噬细胞摄取机制的生理意义（如果有的话）尚不清楚，但假设它可能介导体内变性LDL的降解，从而作为先前描述的在实质细胞中发生的受体介导的天然LDL降解的备用机制。这种清道夫途径可能解释了家族性高胆固醇血症患者巨噬细胞中LDL来源的胆固醇酯的广泛沉积，在这些患者中，由于先天LDL受体的遗传缺陷，LDL降解的实质细胞途径被阻断。
Resident mouse peritoneal macrophages take up and degrade acetylated 125I-labeled low density lipoprotein (125I-acetyl-LDL) in vitro at rates that are 20-fold greater than those for the uptake and degradation of 125I-LDL. The uptake of 125I-acetyl-LDL and its subsequent degradation in lysosomes were attributable to a high-affinity, trypsin-sensitive surface binding site that recognized acetyl-LDL but not native LDL. When 125I-acetyl-LDL was bound to this site at 4.degree. C and the macrophages were subsequently warmed to 37.degree. C, 75% of the cell-bound radioactivity was degraded to mono[125I]iodotyrosine in 1 h. The macrophage binding site also recognized maleylated LDL, maleylated albumin and 2 sulfated polysaccharides (fucoidin and dextran sulfate) indicating that negative charges were important in the binding reaction. A similar binding site was present on rat peritoneal macrophages, guinea pig Kupffer cells and cultured human monocytes but not on human lymphocytes or fibroblasts, mouse fibroblast L cells or Y-1 adrenal adenoma cells or Chinese hamster ovary cells. Uptake and degradation of acetyl-LDL via this binding site stimulated cholesterol esterification 100-fold and produced a 38-fold increase in the cellular content of cholesterol in mouse peritoneal macrophages. Although the physiologic significance, if any, of this macrophage uptake mechanism is not yet known, it is hypothesized that it may mediate the degradation of denatured LDL in the body and thus serve as a backup mechanism for the previously described receptor-mediated degradation of native LDL that occurs in parenchymal cells. Such a scavenger pathway might account for the widespread deposition of LDL-derived cholesteryl esters in macrophages of patients with familial hypercholesterolemia in whom the parenchymal cell pathway for LDL degradation is blocked, owing to a genetic deficiency of receptors for native LDL.