Innerarity T L, Weisgraber K H, Arnold K S, Mahley R W, Krauss R M, Vega G L, Grundy S M
Gladstone Foundation Laboratories for Cardiovascular Disease, University of California, San Francisco 94140-0608.
Proc Natl Acad Sci U S A. 1987 Oct;84(19):6919-23. doi: 10.1073/pnas.84.19.6919.
Previous in vivo turnover studies suggested that retarded clearance of low density lipoproteins (LDL) from the plasma of some hypercholesterolemic patients is due to LDL with defective receptor binding. The present study examined this postulate directly by receptor binding experiments. The LDL from a hypercholesterolemic patient (G.R.) displayed a reduced ability to bind to the LDL receptors on normal human fibroblasts. The G.R. LDL possessed 32% of normal receptor binding activity (approximately equal to 9.3 micrograms of G.R. LDL per ml were required to displace 50% of 125I-labeled normal LDL, vs. approximately equal to 3.0 micrograms of normal LDL per ml). Likewise, the G.R. LDL were much less effective than normal LDL in competing with 125I-labeled normal LDL for cellular uptake and degradation and in stimulating intracellular cholesteryl ester synthesis. The defect in LDL binding appears to be due to a genetic abnormality of apolipoprotein B-100: two brothers of the proband possess LDL defective in receptor binding, whereas a third brother and the proband's son have normally binding LDL. Further, the defect in receptor binding does not appear to be associated with an abnormal lipid composition or structure of the LDL: the chemical and physical properties of the particles were normal, and partial delipidation of the LDL did not alter receptor binding activity. Normal and abnormal LDL subpopulations were partially separated from plasma of two subjects by density-gradient ultracentrifugation, a finding consistent with the presence of a normal and a mutant allele. The affected family members appear to be heterozygous for this disorder, which has been designated familial defective apolipoprotein B-100. These studies indicate that the defective receptor binding results in inefficient clearance of LDL and the hypercholesterolemia observed in these patients.
先前的体内周转研究表明，一些高胆固醇血症患者血浆中低密度脂蛋白（LDL）清除延迟是由于受体结合缺陷的LDL所致。本研究通过受体结合实验直接检验了这一假设。一名高胆固醇血症患者（G.R.）的LDL与正常人成纤维细胞上的LDL受体结合能力降低。G.R.的LDL具有正常受体结合活性的32%（约每毫升9.3微克G.R.的LDL才能取代50%的125I标记的正常LDL，而正常LDL约每毫升3.0微克）。同样，在与125I标记的正常LDL竞争细胞摄取和降解以及刺激细胞内胆固醇酯合成方面，G.R.的LDL比正常LDL的效果要差得多。LDL结合缺陷似乎是由于载脂蛋白B - 100的基因异常：先证者的两个兄弟的LDL受体结合存在缺陷，而第三个兄弟和先证者的儿子的LDL结合正常。此外，受体结合缺陷似乎与LDL的脂质组成或结构异常无关：颗粒的化学和物理性质正常，LDL的部分脱脂也未改变受体结合活性。通过密度梯度超速离心从两名受试者的血浆中部分分离出正常和异常的LDL亚群，这一发现与存在正常和突变等位基因一致。受影响的家庭成员似乎是这种疾病的杂合子，该疾病已被命名为家族性缺陷载脂蛋白B - 100。这些研究表明，受体结合缺陷导致LDL清除效率低下以及这些患者中观察到的高胆固醇血症。
