Lipoproteins and Pathogenesis of Atherosclerosis

  • Daniel Steinberg
Conference paper


Let us start with the assumption that we all agree, along with the NIH Consensus Panel on Lowering Blood Cholesterol (1), that hypercholesterolemia in some way contributes importantly to the progress of human atherosclerosis. The question that remains to be answered is: How? Most investigators have assumed that hypercholesterolemia does its damage as a consequence of a high rate of delivery of cholesterol and other lipids into the artery wall. This is really just a restatement of the Virchow lipid infiltration hypothesis put forward about 100 years ago. However, even a casual look at a complicated human atherosclerotic lesion makes it clear that much more goes on than just the deposition of lipids. There are crucially important elements of cellular proliferation and accumulation of connective tissue matrix materials that contribute significantly to the ultimate stenosis of the vessel.


Foam Cell Artery Wall Familial Hypercholesterolemia Fatty Streak Homozygous Familial Hypercholesterolemia 
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  1. 1.
    Consensus Conference (1985) Lowering blood cholesterol to prevent heart disease. JAMA 253:2080–2090.CrossRefGoogle Scholar
  2. 2.
    Henriksen T, Evensen SA, Carlander B (1979) Injury to human endothelial cells in culture induced by low density lipoproteins. Scand J Clin Lab Invest 39: 361–368.PubMedCrossRefGoogle Scholar
  3. 3.
    Hessler JR, Morel DW, Lewis LJ, Chisolm GM (1983) Lipoprotein oxidation and lipoprotein-induced cytotoxicity. Arteriosclerosis 3:215–222.PubMedCrossRefGoogle Scholar
  4. 4.
    Carvalho A-C, Colman RW, Lees RS (1974) Platelet function in hyperlipoproteinemia. N Engl J Med 290:434–438.PubMedCrossRefGoogle Scholar
  5. 5.
    Steinberg D (1983) Lipoproteins and atherosclerosis. A look back and a look ahead. Arteriosclerosis 3:283–301.PubMedCrossRefGoogle Scholar
  6. 6.
    Watanabe Y (1980) Serial inbreeding of rabbits with hereditary hyperlipemia (WHHL-rabbit). Incidence and development of atherosclerosis. Atherosclerosis 36: 261–268.PubMedCrossRefGoogle Scholar
  7. 7.
    Yamamoto T, Bishop RW, Brown MS, Goldstein J, Russell DW (1986) Deletion in cysteine-rich region of LDL receptor impedes transport to cell surface in WHHL rabbit. Science 232:1230–1237.PubMedCrossRefGoogle Scholar
  8. 8.
    Goldstein JL, Brown MS, Anderson RGW, Russell DW, Schneider WJ (1985) Receptor-mediated endocytosis. Annual Rev Cell Biol 1:1–39.CrossRefGoogle Scholar
  9. 9.
    Fowler S, Shio H, Haley WJ (1979) Characterization of lipid-laden aortic cells from cholesterol-fed rabbits. IV. Investigation of macrophage-like properties of aortic cell populations. Lab Invest 41:372–378.PubMedGoogle Scholar
  10. 10.
    Tsukuda T, Rosenfeld M, Ross R, Gown WM (1986) Immunocyte chemical analysis of cellular components in atherosclerotic lesions. Arteriosclerosis 6:601–613.CrossRefGoogle Scholar
  11. 11.
    Mahley RW (1979) Dietary fat, cholesterol, and accelerated atherosclerosis. Atherosclerosis Rev 5:1–34.Google Scholar
  12. 12.
    Mahley RW, Innerarity TL, Rall Jr SC, Weisgraber KH (1985) Lipoproteins of special significance in atherosclerosis. Insights provided by studies of Type III hyperlipoproteinemias. Ann NY Acad Sci 454:209–221.PubMedCrossRefGoogle Scholar
  13. 13.
    Goldstein J, Ho YK, Basu SK, Brown MS (1979) Binding site on macrophages that mediates uptake and degradation of acetylated low density lipoprotein, producing massive cholesterol deposition. Proc Natl Acad Sci USA 76:333–377.PubMedCrossRefGoogle Scholar
  14. 14.
    Gerrity RG, Naito HK, Richardson M, Schwartz CJ (1979) Dietary induced atherogenesis in swine. Am J Pathol 95:775–793.PubMedGoogle Scholar
  15. 15.
    Fagiotto A, Ross R, Harker L (1984) Studies of hypercholesterolemia in the nonhuman primate. I. Changes that lead to fatty streak formation. Arteriosclerosis 4:323–340.CrossRefGoogle Scholar
  16. 16.
    Gerrity RG (1981) The role of the monocyte in atherogenesis. I. Transition of blood-born monocytes into foam cells in fatty lesions. Am J Pathol 103:181–190.PubMedGoogle Scholar
  17. 17.
    Bevilacqua MP, Pober JS, Wheeler ME, Cotran RS, Gimbrone Jr MA (1985) Interleukin 1 acts on cultured human vascular endothelium to increase the adhesion of polymorphonuclear leukocytes, monocytes, and related leukocyte cell lines. J Cell Invest 76:2003–2011.CrossRefGoogle Scholar
  18. 18.
    Pittman RC, Carew TE, Attie AD, Witztum JL, Watanabe Y, Steinberg D (1982) Receptor-dependent and receptor-independent degradation of low density lipoprotein in normal rabbits and in receptor-deficient mutant rabbits. J Biol Chem 257:7994–8000.PubMedGoogle Scholar
  19. 19.
    Simons LA, Reichl D, Myant NB, Mancini M (1975) The metabolism of the apoprotein of plasma low density lipoprotein in familial hyperbetalipoproteinemia in the homozygous form. Atherosclerosis 21:283–298.PubMedCrossRefGoogle Scholar
  20. 20.
    Carew TE, Chapman MJ, Goldstein S, Steinberg D (1980) Enhanced degradation of trypsin-treated low density lipoprotein by fibroblasts from a patient with familial hypercholesterolemia. Biochim Biophys Acta 529:171–175.Google Scholar
  21. 21.
    Mahley RW, Innearity TL, Weisgraber KH, Oh SY (1979) Altered metabolism (in vivo and vitro) of plasma lipoprotein after selective chemical modification of lysine residues of the apoproteins. J Clin Invest 64:743–750.PubMedCrossRefGoogle Scholar
  22. 22.
    Fogelman AM, Schechter JS, Hokom M, Child JS, Edwards PA (1980) Malondialdehyde alteration of low density lipoprotein leads to cholesterol accumulation in human monocyte-macrophages. Proc Natl Acad Sci USA 77:2214–2218.PubMedCrossRefGoogle Scholar
  23. 23.
    Henriksen T, Mahoney EM, Steinberg D (1981) Enhanced macrophage degradation of low density lipoprotein previously incubated with cultured endothelial cells: recognition by receptors for acetylated low density lipoproteins. Proc Natl Acad Sci USA 78:6499–6503.PubMedCrossRefGoogle Scholar
  24. 24.
    Henriksen T, Mahoney EM, Steinberg D (1982) Enhanced macrophage degradation of biologically modified low density lipoprotein. Arteriosclerosis 3:149–159.Google Scholar
  25. 25.
    Parthasarathy S, Printz DJ, Boyd D, Joy L, Steinberg D (1986) Macrophage oxidation of low density lipoprotein generates a modified form recognized by the scavenger receptor. Arteriosclerosis 6:505–510.PubMedCrossRefGoogle Scholar
  26. 26.
    Steinbrecher UP, Parthasarathy S, Leake DS, Witztum JL, Steinberg D (1984) Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids. Proc Natl Acad Sci USA 81:3883–3887.PubMedCrossRefGoogle Scholar
  27. 27.
    Parthasarathy S, Steinbrecher UP, Barnett J, Witztum JL, Steinberg D (1985) Essential role of phospholipase A2 activity in endothelial cell-induced modification of low density lipoprotein. Proc Natl Acad Sci USA 82: 3000–3004.PubMedCrossRefGoogle Scholar
  28. 28.
    Fong LG, Parthasarathy S, Witztum JL, Steinberg D (1986) Nonenzymatic degradation of aproprotein B-100 during the oxidative modification of low density lipoprotein (submitted to J Biol Chem).Google Scholar
  29. 29.
    Parthasarathy S, Fong SG, Otero D, Steinberg D (1987) Recognition of resolubilized apoproteins from delipid-ated, oxidatively-modified low density lipoprotein (LDL) by the acetyl-LDL receptor. Proc Natl Acad Sci USA 84:537–540.PubMedCrossRefGoogle Scholar
  30. 30.
    Goldstein JL, Hoff JH, Ho YK, Basu SK, Brown MS (1981) Stimulation of cholesteryl ester synthesis in macrophages by extracts of atherosclerotic human aortas and complexes of albumin/cholesteryl ester. Arteriosclerosis 1:210–226.PubMedCrossRefGoogle Scholar
  31. 31.
    Hoff HF, Morton RE (1985) Lipoproteins containing apo B extracted from human aortas: Structure and function. Ann NY Acad Sci 454:183–194.PubMedCrossRefGoogle Scholar
  32. 32.
    Raymond TL, Reynolds SA, Swanson JA (1985) Lipoproteins of the extravascular space: Enhances macrophage degradation of low density lipoproteins from interstitial inflammatory fluid. J Lipid Res 26:1356:1362.Google Scholar
  33. 33.
    Quinn MT, Parthasarathy S, Steinberg D (1985) Endothelial cell-derived chemotactic activity for mouse peritoneal macrophages and the effects of modified forms of low density lipoprotein. Proc Natl Acad Sci USA 82:5949–5953.PubMedCrossRefGoogle Scholar
  34. 34.
    Quinn MT, Parthasarathy S, Fong LG, Steinberg D (1987) Oxidatively modified low density lipoproteins: A potential role in recruitment and retention of monocyte/macrophages during atherogenesis. Proc Natl Acad Sci 84:2995–2998.PubMedCrossRefGoogle Scholar
  35. 35.
    Morel DW, DiCorleto PE, Chisolm GM (1984) Endothelial and smooth muscle cells alter low density lipoprotein in vitro by free radical oxication. Arteriosclerosis 4:357–364.PubMedCrossRefGoogle Scholar
  36. 36.
    Steinberg D (1986) Lipoproteins and atherogenesis: Current concepts. In: Hallgren B, Levin O, Rossner S, Vessby B (eds) Diet and Prevention of Coronary Heart Disease and Cancer. New York: Raven Press, pp. 95–112.Google Scholar

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© Springer-Verlag New York Inc. 1990

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  • Daniel Steinberg

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