Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1988 Sep;82(3):797–802. doi: 10.1172/JCI113681

Catabolic rate of low density lipoprotein is influenced by variation in the apolipoprotein B gene.

T Demant 1, R S Houlston 1, M J Caslake 1, J J Series 1, J Shepherd 1, C J Packard 1, S E Humphries 1
PMCID: PMC303585  PMID: 2901432

Abstract

This study examines the potential influence of genetic variation on the metabolism of LDL. Restriction fragment length polymorphisms (RFLP) of the gene coding for apo B were identified using the endonucleases Xba I, Eco RI, and Msp I in a group of 19 subjects with moderate hyperlipidemia. There was a significant association between the Xba I polymorphism and the total fractional clearance rate (FCR) of LDL. The individuals with the X1X1 genotype had, on average, a 22% higher FCR (P less than 0.025) than those with the genotype X2X2 (X2 allele = presence of Xba I cutting site). This difference was attributable to increased clearance by the receptor-mediated pathway of LDL catabolism. In this group of subjects, there was no association of LDL kinetic parameters and RFLPs of the LDL receptor gene or the AI- CIII- AIV gene cluster. The data suggest that variation in apo B itself, presumably acting through variable binding to the LDL receptor, makes a significant contribution to the rate of catabolism of LDL.

Full text

PDF
797

Images in this article

798Image
on p.798
798Image
on p.798
798Image
on p.798

Selected References

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

  1. Berg K. DNA polymorphism at the apolipoprotein B locus is associated with lipoprotein level. Clin Genet. 1986 Dec;30(6):515–520. doi: 10.1111/j.1399-0004.1986.tb01920.x. [DOI] [PubMed] [Google Scholar]
  2. Brown M. S., Goldstein J. L. Familial hypercholesterolemia: genetic, biochemical and pathophysiologic considerations. Adv Intern Med. 1975;20:273–296. [PubMed] [Google Scholar]
  3. Carlsson P., Darnfors C., Olofsson S. O., Bjursell G. Analysis of the human apolipoprotein B gene; complete structure of the B-74 region. Gene. 1986;49(1):29–51. doi: 10.1016/0378-1119(86)90383-5. [DOI] [PubMed] [Google Scholar]
  4. Carlsson P., Olofsson S. O., Bondjers G., Darnfors C., Wiklund O., Bjursell G. Molecular cloning of human apolipoprotein B cDNA. Nucleic Acids Res. 1985 Dec 20;13(24):8813–8826. doi: 10.1093/nar/13.24.8813. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Coleman R. T., Gonzalez P. A., Funke H., Assmann G., Levy-Wilson B., Frossard P. M. Polymorphisms in the apolipoprotein AI-CIII gene complex. Mol Biol Med. 1986 Jun;3(3):213–228. [PubMed] [Google Scholar]
  6. Deeb S., Failor A., Brown B. G., Brunzell J. D., Albers J. J., Motulsky A. G. Molecular genetics of apolipoproteins and coronary heart disease. Cold Spring Harb Symp Quant Biol. 1986;51(Pt 1):403–409. doi: 10.1101/sqb.1986.051.01.048. [DOI] [PubMed] [Google Scholar]
  7. Feinberg A. P., Vogelstein B. "A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity". Addendum. Anal Biochem. 1984 Feb;137(1):266–267. doi: 10.1016/0003-2697(84)90381-6. [DOI] [PubMed] [Google Scholar]
  8. Goldstein J. L., Brown M. S. The low-density lipoprotein pathway and its relation to atherosclerosis. Annu Rev Biochem. 1977;46:897–930. doi: 10.1146/annurev.bi.46.070177.004341. [DOI] [PubMed] [Google Scholar]
  9. Hegele R. A., Huang L. S., Herbert P. N., Blum C. B., Buring J. E., Hennekens C. H., Breslow J. L. Apolipoprotein B-gene DNA polymorphisms associated with myocardial infarction. N Engl J Med. 1986 Dec 11;315(24):1509–1515. doi: 10.1056/NEJM198612113152403. [DOI] [PubMed] [Google Scholar]
  10. Humphries S. E., Kessling A. M., Horsthemke B., Donald J. A., Seed M., Jowett N., Holm M., Galton D. J., Wynn V., Williamson R. A common DNA polymorphism of the low-density lipoprotein (LDL) receptor gene and its use in diagnosis. Lancet. 1985 May 4;1(8436):1003–1005. doi: 10.1016/s0140-6736(85)91611-3. [DOI] [PubMed] [Google Scholar]
  11. Kesaniemi Y. A., Witztum J. L., Steinbrecher U. P. Receptor-mediated catabolism of low density lipoprotein in man. Quantitation using glucosylated low density lipoprotein. J Clin Invest. 1983 Apr;71(4):950–959. doi: 10.1172/JCI110849. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kessling A. M., Horsthemke B., Humphries S. E. A study of DNA polymorphisms around the human apolipoprotein AI gene in hyperlipidaemic and normal individuals. Clin Genet. 1985 Oct;28(4):296–306. doi: 10.1111/j.1399-0004.1985.tb00403.x. [DOI] [PubMed] [Google Scholar]
  13. Knott T. J., Pease R. J., Powell L. M., Wallis S. C., Rall S. C., Jr, Innerarity T. L., Blackhart B., Taylor W. H., Marcel Y., Milne R. Complete protein sequence and identification of structural domains of human apolipoprotein B. Nature. 1986 Oct 23;323(6090):734–738. doi: 10.1038/323734a0. [DOI] [PubMed] [Google Scholar]
  14. 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]
  15. Kotze M. J., Langenhoven E., Dietzsch E., Retief A. E. A RFLP associated with the low-density lipoprotein receptor gene (LDLR). Nucleic Acids Res. 1987 Jan 12;15(1):376–376. doi: 10.1093/nar/15.1.376. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kunkel L. M., Smith K. D., Boyer S. H., Borgaonkar D. S., Wachtel S. S., Miller O. J., Breg W. R., Jones H. W., Jr, Rary J. M. Analysis of human Y-chromosome-specific reiterated DNA in chromosome variants. Proc Natl Acad Sci U S A. 1977 Mar;74(3):1245–1249. doi: 10.1073/pnas.74.3.1245. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Langer T., Strober W., Levy R. I. The metabolism of low density lipoprotein in familial type II hyperlipoproteinemia. J Clin Invest. 1972 Jun;51(6):1528–1536. doi: 10.1172/JCI106949. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Law A., Wallis S. C., Powell L. M., Pease R. J., Brunt H., Priestley L. M., Knott T. J., Scott J., Altman D. G., Miller G. J. Common DNA polymorphism within coding sequence of apolipoprotein B gene associated with altered lipid levels. Lancet. 1986 Jun 7;1(8493):1301–1303. doi: 10.1016/s0140-6736(86)91222-5. [DOI] [PubMed] [Google Scholar]
  19. Lehrman M. A., Schneider W. J., Südhof T. C., Brown M. S., Goldstein J. L., Russell D. W. Mutation in LDL receptor: Alu-Alu recombination deletes exons encoding transmembrane and cytoplasmic domains. Science. 1985 Jan 11;227(4683):140–146. doi: 10.1126/science.3155573. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Lusis A. J., West R., Mehrabian M., Reuben M. A., LeBoeuf R. C., Kaptein J. S., Johnson D. F., Schumaker V. N., Yuhasz M. P., Schotz M. C. Cloning and expression of apolipoprotein B, the major protein of low and very low density lipoproteins. Proc Natl Acad Sci U S A. 1985 Jul;82(14):4597–4601. doi: 10.1073/pnas.82.14.4597. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Mahley R. W., Innerarity T. L., Pitas R. E., Weisgraber K. H., Brown J. H., Gross E. Inhibition of lipoprotein binding to cell surface receptors of fibroblasts following selective modification of arginyl residues in arginine-rich and B apoproteins. J Biol Chem. 1977 Oct 25;252(20):7279–7287. [PubMed] [Google Scholar]
  22. Packard C. J., McKinney L., Carr K., Shepherd J. Cholesterol feeding increases low density lipoprotein synthesis. J Clin Invest. 1983 Jul;72(1):45–51. doi: 10.1172/JCI110983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Packard C. J., Third J. L., Shepherd J., Lorimer A. R., Morgan H. G., Lawrie T. D. Low density lipoprotein metabolism in a family of familial hypercholesterolemic patients. Metabolism. 1976 Sep;25(9):995–1006. doi: 10.1016/0026-0495(76)90129-3. [DOI] [PubMed] [Google Scholar]
  24. Patsch J. R., Sailer S., Kostner G., Sandhofer F., Holasek A., Braunsteiner H. Separation of the main lipoprotein density classes from human plasma by rate-zonal ultracentrifugation. J Lipid Res. 1974 Jul;15(4):356–366. [PubMed] [Google Scholar]
  25. Priestley L., Knott T., Wallis S., Powell L., Pease R., Simon A., Scott J. RFLP for the human apolipoprotein B gene: I;BamHI. Nucleic Acids Res. 1985 Sep 25;13(18):6789–6789. doi: 10.1093/nar/13.18.6789. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Shepherd J., Bicker S., Lorimer A. R., Packard C. J. Receptor-mediated low density lipoprotein catabolism in man. J Lipid Res. 1979 Nov;20(8):999–1006. [PubMed] [Google Scholar]
  27. Shepherd J., Packard C. J., Bicker S., Lawrie T. D., Morgan H. G. Cholestyramine promotes receptor-mediated low-density-lipoprotein catabolism. N Engl J Med. 1980 May 29;302(22):1219–1222. doi: 10.1056/NEJM198005293022202. [DOI] [PubMed] [Google Scholar]
  28. Shoulders C. C., Myant N. B., Sidoli A., Rodriguez J. C., Cortese C., Baralle F. E., Cortese R. Molecular cloning of human LDL apolipoprotein B cDNA. Evidence for more than one gene per haploid genome. Atherosclerosis. 1985 Dec;58(1-3):277–289. doi: 10.1016/0021-9150(85)90073-5. [DOI] [PubMed] [Google Scholar]
  29. Slater H. R., McKinney L., Packard C. J., Shepherd J. Contribution of the receptor pathway to low density lipoprotein catabolism in humans. New methods for quantitation. Arteriosclerosis. 1984 Nov-Dec;4(6):604–613. doi: 10.1161/01.atv.4.6.604. [DOI] [PubMed] [Google Scholar]
  30. Sparks J. D., Sparks C. E. Apolipoprotein B and lipoprotein metabolism. Adv Lipid Res. 1985;21:1–46. doi: 10.1016/b978-0-12-024921-3.50007-1. [DOI] [PubMed] [Google Scholar]
  31. Talmud P. J., Barni N., Kessling A. M., Carlsson P., Darnfors C., Bjursell G., Galton D., Wynn V., Kirk H., Hayden M. R. Apolipoprotein B gene variants are involved in the determination of serum cholesterol levels: a study in normo- and hyperlipidaemic individuals. Atherosclerosis. 1987 Sep;67(1):81–89. doi: 10.1016/0021-9150(87)90267-x. [DOI] [PubMed] [Google Scholar]
  32. Tolleshaug H., Goldstein J. L., Schneider W. J., Brown M. S. Posttranslational processing of the LDL receptor and its genetic disruption in familial hypercholesterolemia. Cell. 1982 Oct;30(3):715–724. doi: 10.1016/0092-8674(82)90276-8. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES