Type III Hyperlipoproteinemia: A Focus on Lipoprotein Receptor-Apolipoprotein E2 Interactions

  • Thomas L. Innerarity
  • David Y. Hui
  • Thomas P. Bersot
  • Robert W. Mahley
Part of the Advances in Experimetal Medicine and Biology book series (AEMB, volume 201)


Type III hyperlipoproteinemia is a genetic abnormality characterized by elevated levels of plasma cholesterol and triglycerides and by the presence of cholesterol-enriched β-migrating very low density lipoproteins (β-VLDL). Patients suffering from this abnormality develop tuberous xanthomas and premature atherosclerosis. The expression of the disease depends upon the interaction of a known apoprotein genotype with other genetic and/or environmental factors; thus, type III hyperlipoproteinemia is an especially good model for furthering our understanding of the interplay of genetic and environmental factors in the regulation of lipoprotein metabolism and the development of atherosclerosis.


Receptor Binding Lipoprotein Receptor Receptor Binding Domain Chylomicron Remnant Familial Type 
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  1. 1.
    R. W. Mahley and B. Angelin, Type III hyperlipoproteinemia. Recent insights into the genetic defect of familial dysbetalipoproteinemia, Adv. Intern. Med. 29:385–411, (1984).PubMedGoogle Scholar
  2. 2.
    M. S. Brown, J. L. Goldstein, and D. S. Fredrickson, Familial type 3 hyperlipoproteinemia (dysbetalipoproteinemia), in: “The Metabolic Basis of Inherited Disease,” 5th edition, J. B. Stanbury, J. B. Wyngaarden, D. S. Fredrickson, J. L. Goldstein, and M. S. Brown, eds., McGraw-Hill, New York (1983).Google Scholar
  3. 3.
    R. J. Havel, Familial dysbetalipoproteinemia. New aspects of patho-genesis and diagnosis, Med. Clin. North Am. 66:441–454 (1982).PubMedGoogle Scholar
  4. 4.
    R. W. Mahley, Atherogenic lipoproteins and coronary artery disease: concepts derived from recent advances in cellular and molecular biology, Circulation 72:in press (1985).CrossRefGoogle Scholar
  5. 5.
    D. Y. Hui, W. J. Brecht, E. A. Hall, G. Friedman, T. L. Innerarity, and R. W. Mahley, Purification of the Hepatic Apolipoprotein E Receptor, Submitted for publication.Google Scholar
  6. 6.
    G. Utermann, M. Hees, and A. Steinmetz, Polymorphism of apolipoprotein E and occurrence of dysbetalipoproteinaemia in man, Nature 269:604–607 (1977).PubMedCrossRefGoogle Scholar
  7. 7.
    V. I. Zannis and J. L. Breslow, Human very low density lipoprotein apolipoprotein E isoprotein polymorphism is explained by genetic variation and post-translational modification, Biochemistry 20:1033–1041 (1981).PubMedCrossRefGoogle Scholar
  8. 8.
    K. H. Weisgraber, T. L. Innerarity, and R. W. Mahley, Abnormal lipoprotein receptor-binding activity of the human E apoprotein due to cysteine-arginine interchange at a single site, J. Biol. Chem. 257:2518–2521 (1982).PubMedGoogle Scholar
  9. 9.
    R. W. Mahley, T. L. Innerarity, S. C. Rail, Jr., and K. H. Weisgraber, Plasma lipoproteins: apolipoprotein structure and function, J. Lipid Res. 25:1277–1294 (1984).PubMedGoogle Scholar
  10. 10.
    T. Yamamura, A. Yamamoto, S. Nambu, and K. Hiramori, Plasma apolipoprotein E mutants associated with atherosclerotic diseases, Arteriosclerosis 4:549a (1984).Google Scholar
  11. 11.
    T. Yamamura, A. Yamamoto, T. Sumiyoshi, K. Hiramori, Y. Nishioeda, and S. Nambu, New mutants of apolipoprotein E associated with atherosclerotic diseases but not to type III hyperlipoproteinemia, J. Clin. Invest. 74:1229–1237 (1984).PubMedCrossRefGoogle Scholar
  12. 12.
    R. J. Havel, Y.-S. Chao, E. E. Windier, L. Kotite, and L. S. S. Guo, Isoprotein specificity in the hepatic uptake of apolipoprotein E and the pathogenesis of familial dysbetalipoproteinemia, Proc. Natl. Acad. Sci. USA 77:4349–4353 (1980).PubMedCrossRefGoogle Scholar
  13. 13.
    T. L. Innerarity, E. J. Friedlander, S. C. Rail, Jr., K. W. Weisgraber, and R. W. Mahley, The receptor binding domain of human apolipoprotein E: binding of apolipoprotein E fragments, J. Biol. Chem. 258:12341–12347 (1983).PubMedGoogle Scholar
  14. 14.
    K. H. Weisgraber, T. L. Innerarity, K. J. Harder, R. W. Mahley, R. W. Milne, Y. L. Marcel, and J. T. Sparrow, The receptor binding domain of human apolipoprotein E: monoclonal antibody inhibition of binding, J. Biol. Chem. 258:12348–12354 (1983).PubMedGoogle Scholar
  15. 15.
    R. W. Mahley and T. L. Innerarity, Lipoprotein receptors and cholesterol homeostasis, Biochim. Biophys. Acta 737:197–222 (1983).PubMedCrossRefGoogle Scholar
  16. 16.
    T. L. Innerarity, K. H. Weisgraber, K. S. Arnold, S. C. Rail, Jr., and R. W. Mahley, Normalization of receptor binding of apolipoprotein E2. Evidence for modulation of the binding site conformation, J. Biol. Chem. 259:7261–7267 (1984).PubMedGoogle Scholar
  17. 17.
    T. Yamamoto, C. G. Davis, M. S. Brown, W. J. Schneider, M. L. Casey, J. L. Goldstein, and D. W. Russell, The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA, Cell 39:27–38 (1984).PubMedCrossRefGoogle Scholar
  18. 18.
    J. L. Goldstein, M. S. Brown, R. G. W. Anderson, D. W. Russell, and W. J. Schneider, Receptor-mediated endocytosis: concepts emerging from the LDL receptor system, Annu. Rev. Cell Biol., in press (1985).Google Scholar
  19. 19.
    M. S. Brown, T. F. Deuel, S. K. Basu, J. L. Goldstein, Inhibition of the binding of low density lipoprotein to its cell surface receptor in human fibroblasts by positively charged proteins, J. Supramol. Struct. 8:223–234 (1978).PubMedCrossRefGoogle Scholar
  20. 20.
    G. Utermann, N. Pruin, and A. Steinmetz, Polymorphism of apolipoprotein E. III. Effect of a single polymorphic gene locus on plasma lipid levels in man, Clin. Genet. 15:63–72 (1979).PubMedCrossRefGoogle Scholar
  21. 21.
    R. W. Mahley, T. L. Innerarity, S. C. Rail, Jr., and K. H. Weisgraber, Lipoproteins of special significance in atherosclerosis: insights provided by studies of type III hyperlipoproteinemia, Ann. NY Acad. Sci. USA, 454:209–221 (1985).CrossRefGoogle Scholar
  22. 22.
    S. M. Grundy, Cholesterol metabolism in man, West. J. Med. 128:13–25 (1978).PubMedGoogle Scholar
  23. 23.
    C. Ehnholm, R. W. Mahley, D. A. Chappell, K. H. Weisgraber, E. Ludwig, and J. L. Witztum, The role of apolipoprotein E in the lipo-lytic conversion of ß-very low density lipoproteins to low density lipoproteins in type III hyperlipoproteinemia, Proc. Natl. Acad. Sci. USA 81:5566–5570 (1984).PubMedCrossRefGoogle Scholar
  24. 24.
    M. S. Brown and J. L. Goldstein, Lipoprotein receptors in the liver. Control signals for plasma cholesterol traffic, J. Clin. Invest. 72:743–747 (1983).PubMedCrossRefGoogle Scholar
  25. 25.
    B. Angelin, C. A. Raviola, T. L. Innerarity, and R. W. Mahley, Regulation of hepatic lipoprotein receptors in the dog. Rapid regulation of apolipoprotein B,E receptors, but not of apolipoprotein E receptors, by intestinal lipoproteins and bile acids, J. Clin. Invest. 71:816–831 (1983).PubMedCrossRefGoogle Scholar
  26. 26.
    W. R. Hazzard, Primary type III hyperlipoproteinemia, in “Hyper-lipidemia Diagnosis and Therapy,” B.M. Rifkind and R.I. Levy, eds., Grune & Stratton, New York (1977).Google Scholar
  27. 27.
    R. S. Kushwaha, W. R. Hazzard, C. Gagne, A. Chait, J. J. Albers, Type III hyperlipoproteinemia: paradoxical hypolipidemic response to estrogen, Ann. Intern. Med. 87:517–525 (1977).PubMedGoogle Scholar
  28. 28.
    E. E. Windier, P. T. Kovanen, Y. S. Chao, M. S. Brown, R. J. Havel, and J. L. Goldstein, The estradiol-stimulated lipoprotein receptor of rat liver. A binding site that mediates the uptake of rat lipoproteins containing apoproteins B and E, J. Biol. Chem. 255:10464–10471 (1980).Google Scholar
  29. 29.
    D. Y. Hui, T. L. Innerarity, and R. W. Mahley, Defective hepatic lipoprotein receptor binding of ß-very low density lipoproteins from type III hyperlipoproteinemic patients. Importance of apolipoprotein E, J. Biol. Chem. 259:860–869 (1984).PubMedGoogle Scholar
  30. 30.
    D. Y. Hui, T. L. Innerarity, R. W. Milne, Y. L. Marcel, and R. W. Mahley, Binding of chylomicron remnants and ß-very low density lipoproteins to hepatic and extrahepatic lipoprotein receptors. Aprocess independent of apolipoprotein B48, J. Biol. Chem. 259:15060–15068 (1984).PubMedGoogle Scholar
  31. 31.
    S. C. Rall, Jr., K. H. Weisgraber, T. L. Innerarity, R. W. Mahley, and G. Assmann, Identical structural and receptor binding defects in apolipoprotein E2 in hypo-, normo-, and hypercholesterolemic dysbetalipoproteinemia, J. Clin. Invest. 71:1023–1031 (1983).PubMedCrossRefGoogle Scholar
  32. 32.
    R. I. Levy, D. S. Fredrickson, R. Shulman, D. W. Bilheimer, J. L. Breslow, N. J. Stone, S. E. Lux, H. R. Sloan, R. M. Kraus, and P. N. Herbert, Dietary and drug treatment of primary hyperlipopro-teinemia, Ann. Intern. Med. 77:267–294 (1972).Google Scholar
  33. 33.
    S. C. Rall, Jr., K. H. Weisgraber, and R. W. Mahley, Human apolipoprotein E. The complete amino acid sequence, J. Biol. Chem. 257:4171–4178 (1982).PubMedGoogle Scholar
  34. 34.
    S. H. Gianturco, A. M. Gotto, Jr., S.-L. C. Hwang, J. B. Karlin, A. H. Y. Lin, S. C. Prasad, and W. A. Bradley, Apolipoprotein E mediates uptake o, S f 100–400 hypertriglyceridemic very low density lipoproteins by the low density lipoprotein receptor pathway in normal human fibroblasts, J. Biol. Chem. 258:4526–4533 (1983).PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1986

Authors and Affiliations

  • Thomas L. Innerarity
    • 1
  • David Y. Hui
    • 1
  • Thomas P. Bersot
    • 1
  • Robert W. Mahley
    • 1
  1. 1.Gladstone Foundation Laboratories for Cardiovascular Disease Cardiovascular Research Institute, Departments of Pathology and MedicineUniversity of CaliforniaSan FranciscoUSA

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