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.