Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1987 Oct;84(19):6919–6923. doi: 10.1073/pnas.84.19.6919

Familial defective apolipoprotein B-100: low density lipoproteins with abnormal receptor binding.

T L Innerarity 1, K H Weisgraber 1, K S Arnold 1, R W Mahley 1, R M Krauss 1, G L Vega 1, S M Grundy 1
PMCID: PMC299196  PMID: 3477815

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.

Full text

PDF
6919

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. BARTLETT G. R. Phosphorus assay in column chromatography. J Biol Chem. 1959 Mar;234(3):466–468. [PubMed] [Google Scholar]
  2. Blackhart B. D., Ludwig E. M., Pierotti V. R., Caiati L., Onasch M. A., Wallis S. C., Powell L., Pease R., Knott T. J., Chu M. L. Structure of the human apolipoprotein B gene. J Biol Chem. 1986 Nov 25;261(33):15364–15367. [PubMed] [Google Scholar]
  3. Brown M. S., Goldstein J. L. A receptor-mediated pathway for cholesterol homeostasis. Science. 1986 Apr 4;232(4746):34–47. doi: 10.1126/science.3513311. [DOI] [PubMed] [Google Scholar]
  4. Brown M. S., Goldstein J. L. Lipoprotein receptors in the liver. Control signals for plasma cholesterol traffic. J Clin Invest. 1983 Sep;72(3):743–747. doi: 10.1172/JCI111044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Elovson J., Jacobs J. C., Schumaker V. N., Puppione D. L. Molecular weights of apoprotein B obtained from human low-density lipoprotein (apoprotein B-PI) and from rat very low density lipoprotein (apoprotein B-PIII). Biochemistry. 1985 Mar 12;24(6):1569–1578. doi: 10.1021/bi00327a042. [DOI] [PubMed] [Google Scholar]
  6. Goldstein J. L., Basu S. K., Brown M. S. Receptor-mediated endocytosis of low-density lipoprotein in cultured cells. Methods Enzymol. 1983;98:241–260. doi: 10.1016/0076-6879(83)98152-1. [DOI] [PubMed] [Google Scholar]
  7. Goldstein J. L., Hazzard W. R., Schrott H. G., Bierman E. L., Motulsky A. G. Hyperlipidemia in coronary heart disease. I. Lipid levels in 500 survivors of myocardial infarction. J Clin Invest. 1973 Jul;52(7):1533–1543. doi: 10.1172/JCI107331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Grundy S. M., Vega G. L. Influence of mevinolin on metabolism of low density lipoproteins in primary moderate hypercholesterolemia. J Lipid Res. 1985 Dec;26(12):1464–1475. [PubMed] [Google Scholar]
  9. Innerarity T. L., Mahley R. W. Enhanced binding by cultured human fibroblasts of apo-E-containing lipoproteins as compared with low density lipoproteins. Biochemistry. 1978 Apr 18;17(8):1440–1447. doi: 10.1021/bi00601a013. [DOI] [PubMed] [Google Scholar]
  10. Innerarity T. L., Pitas R. E., Mahley R. W. Lipoprotein-receptor interactions. Methods Enzymol. 1986;129:542–565. doi: 10.1016/0076-6879(86)29091-6. [DOI] [PubMed] [Google Scholar]
  11. Innerarity T. L., Weisgraber K. H., Rall S. C., Jr, Mahley R. W. Functional domains of apolipoprotein E and apolipoprotein B. Acta Med Scand Suppl. 1987;715:51–59. doi: 10.1111/j.0954-6820.1987.tb09903.x. [DOI] [PubMed] [Google Scholar]
  12. Kita T., Brown M. S., Bilheimer D. W., Goldstein J. L. Delayed clearance of very low density and intermediate density lipoproteins with enhanced conversion to low density lipoprotein in WHHL rabbits. Proc Natl Acad Sci U S A. 1982 Sep;79(18):5693–5697. doi: 10.1073/pnas.79.18.5693. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Knott T. J., Rall S. C., Jr, Innerarity T. L., Jacobson S. F., Urdea M. S., Levy-Wilson B., Powell L. M., Pease R. J., Eddy R., Nakai H. Human apolipoprotein B: structure of carboxyl-terminal domains, sites of gene expression, and chromosomal localization. Science. 1985 Oct 4;230(4721):37–43. doi: 10.1126/science.2994225. [DOI] [PubMed] [Google Scholar]
  14. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  15. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  16. Mahley R. W., Innerarity T. L. Lipoprotein receptors and cholesterol homeostasis. Biochim Biophys Acta. 1983 May 24;737(2):197–222. doi: 10.1016/0304-4157(83)90001-1. [DOI] [PubMed] [Google Scholar]
  17. Marcel Y. L., Innerarity T. L., Spilman C., Mahley R. W., Protter A. A., Milne R. W. Mapping of human apolipoprotein B antigenic determinants. Arteriosclerosis. 1987 Mar-Apr;7(2):166–175. doi: 10.1161/01.atv.7.2.166. [DOI] [PubMed] [Google Scholar]
  18. Meddings J. B., Dietschy J. M. Regulation of plasma levels of low-density lipoprotein cholesterol: interpretation of data on low-density lipoprotein turnover in man. Circulation. 1986 Oct;74(4):805–814. doi: 10.1161/01.cir.74.4.805. [DOI] [PubMed] [Google Scholar]
  19. Shen M. M., Krauss R. M., Lindgren F. T., Forte T. M. Heterogeneity of serum low density lipoproteins in normal human subjects. J Lipid Res. 1981 Feb;22(2):236–244. [PubMed] [Google Scholar]
  20. Vega G. L., Grundy S. M. In vivo evidence for reduced binding of low density lipoproteins to receptors as a cause of primary moderate hypercholesterolemia. J Clin Invest. 1986 Nov;78(5):1410–1414. doi: 10.1172/JCI112729. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Weisgraber K. H., Rall S. C., Jr Human apolipoprotein B-100 heparin-binding sites. J Biol Chem. 1987 Aug 15;262(23):11097–11103. [PubMed] [Google Scholar]
  22. Wilson P. W., Garrison R. J., Castelli W. P., Feinleib M., McNamara P. M., Kannel W. B. Prevalence of coronary heart disease in the Framingham Offspring Study: role of lipoprotein cholesterols. Am J Cardiol. 1980 Oct;46(4):649–654. doi: 10.1016/0002-9149(80)90516-0. [DOI] [PubMed] [Google Scholar]
  23. Yamada N., Shames D. M., Stoudemire J. B., Havel R. J. Metabolism of lipoproteins containing apolipoprotein B-100 in blood plasma of rabbits: heterogeneity related to the presence of apolipoprotein E. Proc Natl Acad Sci U S A. 1986 May;83(10):3479–3483. doi: 10.1073/pnas.83.10.3479. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Young S. G., Bertics S. J., Curtiss L. K., Dubois B. W., Witztum J. L. Genetic analysis of a kindred with familial hypobetalipoproteinemia. Evidence for two separate gene defects: one associated with an abnormal apolipoprotein B species, apolipoprotein B-37; and a second associated with low plasma concentrations of apolipoprotein B-100. J Clin Invest. 1987 Jun;79(6):1842–1851. doi: 10.1172/JCI113026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Young S. G., Bertics S. J., Curtiss L. K., Witztum J. L. Characterization of an abnormal species of apolipoprotein B, apolipoprotein B-37, associated with familial hypobetalipoproteinemia. J Clin Invest. 1987 Jun;79(6):1831–1841. doi: 10.1172/JCI113025. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES