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Familial defective apolipoprotein B-100: low density lipoproteins with abnormal receptor binding
T L Innerarity1, K H Weisgraber, K S Arnold
1Gladstone Foundation Laboratories for Cardiovascular Disease, University of California, San Francisco 94140-0608.
Insights
Low-density lipoproteins (LDL) from some hypercholesterolemic patients show defective receptor binding, leading to slower clearance and high cholesterol. This genetic defect in apolipoprotein B-100 causes familial defective apolipoprotein B-100.
Area of Science:
- Biochemistry
- Genetics
- Molecular Biology
Background:
- Previous in vivo studies suggested impaired low-density lipoprotein (LDL) clearance in hypercholesterolemia may stem from defective LDL receptor binding.
- This study directly investigates the receptor binding hypothesis using in vitro experiments.
Observation:
- LDL isolated from a hypercholesterolemic patient (G.R.) exhibited significantly reduced binding affinity to LDL receptors on normal human fibroblasts.
- G.R. LDL demonstrated only 32% of normal receptor binding activity, requiring substantially more LDL to displace labeled normal LDL.
- G.R. LDL was less effective in competing for cellular uptake and degradation, and in stimulating cholesteryl ester synthesis compared to normal LDL.
Findings:
- The observed defect in LDL receptor binding is linked to a genetic abnormality in apolipoprotein B-100.
- Affected individuals within the patient's family exhibited this defective binding, suggesting a hereditary component.
- The defect does not correlate with abnormal lipid composition or structure of the LDL particles.
- Density-gradient ultracentrifugation separated normal and abnormal LDL subpopulations, supporting the presence of both normal and mutant alleles.
Implications:
- The findings identify familial defective apolipoprotein B-100 as a cause of hypercholesterolemia due to inefficient LDL clearance.
- This research clarifies the molecular basis of certain hypercholesterolemic conditions, linking genetic defects to metabolic dysfunction.
- Understanding this specific defect provides insights into lipoprotein metabolism and receptor interactions, potentially informing therapeutic strategies.
Abstract:
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.