Role of lipoproteins in progression of coronary arteriosclerosis

  • T. J. C. Van Berkel
Part of the Developments in Cardiovascular Medicine book series (DICM, volume 180)


Lipoproteins are responsible for the transport of cholesterol (esters) and triglycerides. Chylomicron-(remnants), VLDL-remnants (β-VLDL) and (modified) LDL are considered to be atherogenic while high levels of HDL do protect against arteriosclerosis. The liver plays a decisive role in the regulation of the plasma levels of atherogenic lipoproteins. The primary liver interaction site of chylomicron remnants and VLDL remnants (β-VLDL) is still unidentified, whereas the subsequent cellular uptake is likely to be mediated in concert by the LDL-receptor-related protein and the LDL receptor. The nature of the primary interaction site of remnants (remnant receptor) might be a liver-specific proteoglycan or a liver-specific protein. Atherogenic modified LDL can be recognized by a family of scavenger receptors. A newly identified 95-kDa protein forms the most likely candidate for mediating the in-vivo uptake of oxidized LDL from the circulation and may, therefore, protect the body against the presence of oxidized LDL in the blood compartment. HDL do pick up peripheral cholesterol and deliver cholesterol (esters) to the liver. The antiatherogenic action of HDL may reside in specific subfractions containing specific apolipoproteins.


Bile Acid Kupffer Cell Cholesteryl Ester Scavenger Receptor Reverse Cholesterol Transport 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Dietschy JM, Turley SD, Spady DK. Role of liver in the maintenance of cholesterol and low density lipoprotein homeostasis in different animal species, including humans. J Lipid Res. 1993;34:1637–59.PubMedGoogle Scholar
  2. 2.
    Redgrave TG, Small DM. Quantitation of the transfer of surface phospholipid of chylomicrons to the high density lipoprotein fraction during the catabolism of chylomicrons in the rat. J Clin Invest. 1979;64:162–71.PubMedCrossRefGoogle Scholar
  3. 3.
    Windler E, Chao Y, Havel RJ. Determinants of hepatic uptake of triglyceride-rich lipoproteins and their remnants in the rat. J Biol Chem. 1980;255:5475–80.PubMedGoogle Scholar
  4. 4.
    Mulder M, Lombardi P, Jansen H, van Berkel TJC, Frants RR, Havekes LM. Low density lipoprotein receptor internalizes low density and very low density lipoproteins that are bound to heparan sulfate proteoglycans via lipoprotein lipase. J Biol Chem. 1993;268:9369–75.PubMedGoogle Scholar
  5. 5.
    Olivecrona T, Bengtsson-Olivecrona G. Lipases involved in lipoprotein metabolism. Curr Opin Lipidol. 1990;1:116–21.CrossRefGoogle Scholar
  6. 6.
    Vilella E, Joven J. Lipoprotein lipase binding to plasma lipoproteins. Med Sci Res. 1991;19:111–12.Google Scholar
  7. 7.
    van Dijk MC, Ziere GJ, Boers W, Linthorst C, Bijsterbosch MK, van Berkel TJC. Recognition of chylomicron remnants and beta-migrating very-low-density lipoproteins by the remnant receptor of parenchymal liver cells is distinct from the liver alpha 2-macroglobulin-recognition site. Biochem J. 1991;279:863–70.PubMedGoogle Scholar
  8. 8.
    Gudmundsen O, Berg T, Roos N, Nenseter MS. Hepatic uptake of beta-VLDL in cholesterol-fed rabbits. J Lipid Res. 1993;34:589–600.PubMedGoogle Scholar
  9. 9.
    Yen FT, Mann CJ, Guermani LM, et al. Identification of a lipolysis-stimulated receptor that is distinct from the LDL receptor and the LDL receptor-related protein. Biochemistry. 1994;33:1172–80.PubMedCrossRefGoogle Scholar
  10. 10.
    Choi SY, Cooper AD. A comparison of the roles of the low density lipoprotein (LDL) receptor and the LDL receptor-related protein/alpha 2-macroglobulin receptor in chylomicron remnant removal in the mouse in vivo. J Biol Chem. 1993;268:15804–11.PubMedGoogle Scholar
  11. 11.
    Nykjaer A, Bengtsson-Olivecrona G, Lookene A, et al. The alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein binds lipoprotein lipase and beta-migrating very low density lipoprotein associated with the lipase. J Biol Chem. 1993;268:15048–55.PubMedGoogle Scholar
  12. 12.
    Jäckle S, Huber C, Moestrup S, Gliemann J, Beisiegel U. In vivo removal of beta-VLDL, chylomicron remnants, and alpha 2-macroglobulin in the rat. J Lipid Res. 1993;34:309–15.PubMedGoogle Scholar
  13. 13.
    van Dijk MC, Kruijt JK, Boers W, Linthorst C, van Berkel TJC. Distinct properties of the recognition sites for beta-very low density lipoprotein (remnant receptor) and alpha 2-macroglobulin (low density lipoprotein receptor-related protein) on rat parenchymal cells. J Biol Chem. 1992;267:17732–7.PubMedGoogle Scholar
  14. 14.
    van Berkel TJC, Kruijt JK, Scheek LM, Groot PH. Effect of apolipoproteins E and C-III on the interaction of chylomicrons with parenchymal and non-parenchymal cells from rat liver. Biochem J. 1983;216:71–80.PubMedGoogle Scholar
  15. 15.
    Ziere GJ, Bijsterbosch MK, van Berkel TJC. Removal of 14 N-terminal amino acids of lactoferrin enhances its affinity for parenchymal liver cells and potentiates the inhibition of beta-very low density lipoprotein binding. J Biol Chem. 1993;268:27069–75.PubMedGoogle Scholar
  16. 16.
    Kita T, Goldstein JL, Brown MS, Watanabe Y, Hornick CA, Havel RJ. Hepatic uptake of chylomicron remnants in WHHL rabbits: a mechanism genetically distinct from the low density lipoprotein receptor. Proc Natl Acad Sci USA. 1982;79:3623–7.PubMedCrossRefGoogle Scholar
  17. 17.
    Rubinsztein DC, Cohen JC, Berger GM, van der Westhuyzen DR, Coetzee GA, Gevers W. Chylomicron remnant clearance from the plasma is normal in familial hypercholesterolemic homozygotes with defined receptor defects. J Clin Invest. 1990;86:1306–12.PubMedCrossRefGoogle Scholar
  18. 18.
    Demacker PN, van Heijst PJ, Stalenhoef AF. A study of the chylomicron metabolism in WHHL rabbits after fat loading. Discrepancy between results based on measurement of apoprotein B-48 or retinyl palmitate. Biochem J. 1992;285:641–6.PubMedGoogle Scholar
  19. 19.
    Bowler A, Redgrave TG, Mamo JC. Chylomicron-remnant clearance in homozygote and heterozygote Watanabe-heritable-hyperlipidaemic rabbits is defective. Lack of evidence for an independent chylomicron-remnant receptor. Biochem J. 1991;276:381–6.PubMedGoogle Scholar
  20. 20.
    Willnow TE, Goldstein JL, Orth K, Brown MS, Herz J. Low density lipoprotein receptor-related protein and gp330 bind similar ligands, including plasminogen activator-inhibitor complexes and lactoferrin, an inhibitor of chylomicron remnant clearance. J Biol Chem. 1992;267:26172–80.PubMedGoogle Scholar
  21. 21.
    Warshawsky I, Bu G, Schwartz AL. Identification of domains on the 39-kDa protein that inhibit the binding of ligands to the low density lipoprotein receptor-related protein. J Biol Chem. 1993;268:22046–54.PubMedGoogle Scholar
  22. 22.
    Warshawsky I, Bu G, Schwartz AL. Binding analysis of amino-terminal and carboxyl-terminal regions of the 39-kDa protein to the low density lipoprotein receptor-related protein. J Biol Chem. 1994;269:3325–30.PubMedGoogle Scholar
  23. 23.
    Van Leuven F, Cassiman JJ, Van den Berghe H. Functional modifications of alpha 2-macroglobulin by primary amines. I. Characterization of alpha 2 M after derivatization by methylamine and by factor XIII. J Biol Chem. 1981;256:9016–22.PubMedGoogle Scholar
  24. 24.
    Bu G, Maksymovitch EA, Schwartz AL. Receptor-mediated endocytosis of tissue-type plasminogen activator by low density lipoprotein receptor-related protein on human hepatoma HepG2 cells. J Biol Chem. 1993;268:13002–9.PubMedGoogle Scholar
  25. 25.
    Bu G, Williams S, Strickland DK, Schwartz AL. Low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor is an hepatic receptor for tissue-type plasminogen activator. Proc Natl Acad Sci USA. 1992;89:7427–31.PubMedCrossRefGoogle Scholar
  26. 26.
    Bu G, Morton PA, Schwartz AL. Identification and partial characterization by chemical cross-linking of a binding protein for tissue-type plasminogen activator (t-PA) on rat hepatoma cells. A plasminogen activator inhibitor type 1-independent t-PA receptor. J Biol Chem. 1992;267:15595–602.PubMedGoogle Scholar
  27. 27.
    Kounnas MZ, Henkin J, Argraves WS, Strickland DK. Low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor mediates cellular uptake of pro-urokinase. J Biol Chem. 1993;268:21862–7.PubMedGoogle Scholar
  28. 28.
    Orth K, Madison EL, Gething MJ, Sambrook JF, Herz J. Complexes of tissue-type plasminogen activator and its serpin inhibitor plasminogen-activator inhibitor type 1 are internalized by means of the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor. Proc Natl Acad Sci USA. 1992;89:7422–6.PubMedCrossRefGoogle Scholar
  29. 29.
    Kounnas MZ, Morris RE, Thompson MR, FitzGerald DJ, Strickland DK, Saelinger CB. The alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein binds and internalizes Pseudomonas exotoxin A. J Biol Chem. 1992;267:12420–3.PubMedGoogle Scholar
  30. 30.
    Nimpf J, Stifani S, Bilous PT, Schneider WJ. The somatic cell-specific low density lipoprotein receptor-related protein of the chicken. Close kinship to mammalian low density lipoprotein receptor gene family members. J Biol Chem. 1994;269:212–9.PubMedGoogle Scholar
  31. 31.
    Chappell DA, Fry GL, Waknitz MA, et al. Lipoprotein lipase induces catabolism of normal triglyceride-rich lipoproteins via the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor in vitro. A process facilitated by cell-surface proteoglycans. J Biol Chem. 1993;268:14168–75.PubMedGoogle Scholar
  32. 32.
    Kounnas MZ, Chappell DA, Strickland DK, Argraves WS. Glycoprotein 330, a member of the low density lipoprotein receptor family, binds lipoprotein lipase in vitro. J Biol Chem. 1993;268:14176–81.PubMedGoogle Scholar
  33. 33.
    Kowal RC, Herz J, Goldstein JL, Esser V, Brown MS. Low density lipoprotein receptor-related protein mediates uptake of cholesteryl esters derived from apoprotein E-enriched lipoproteins. Proc Natl Acad Sci USA. 1989;86:5810–14.PubMedCrossRefGoogle Scholar
  34. 34.
    Ji ZS, Brecht WJ, Miranda RD, Hussain MM, Innerarity TL, Mahley RW. Role of heparan sulfate proteoglycans in the binding and uptake of apolipoprotein E-enriched remnant lipoproteins by cultured cells. J Biol Chem. 1993;268:10160–7.PubMedGoogle Scholar
  35. 35.
    Bihain BE, Yen FT. Free fatty acids activate a high-affinity saturable pathway for degradation of low-density lipoproteins in fibroblasts from a subject homozygous for familial hypercholesterolemia. Biochemistry. 1992;31:4628–36.PubMedCrossRefGoogle Scholar
  36. 36.
    Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993;362:801–9.PubMedCrossRefGoogle Scholar
  37. 37.
    Brown MS, Basu SK, Falck JR, Ho YK, Goldstein JL. The scavenger cell pathway for lipoprotein degradation: specificity of the binding site that mediates the uptake of negatively-charged LDL by macrophages. J Supramol Struct. 1980;13:67–81.PubMedCrossRefGoogle Scholar
  38. 38.
    van Berkel TJC, Nagelkerke JF, Harkes L, Kruijt JK. Processing of acetylated human low-density lipoprotein by parenchymal and non-parenchymal liver cells. Involvement of calmodulin? Biochem J. 1982;208:493–503.PubMedGoogle Scholar
  39. 39.
    Nagelkerke JF, Barto KP, van Berkel TJ. In vivo and in vitro uptake and degradation of acetylated low density lipoprotein by rat liver endothelial, Kupffer, and parenchymal cells. J Biol Chem. 1983;258:12221–7.PubMedGoogle Scholar
  40. 40.
    Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med. 1989;320:915–24.PubMedCrossRefGoogle Scholar
  41. 41.
    van Berkel TJC, De Rijke YB, Kruijt JK. Different fate in vivo of oxidatively modified low density lipoprotein and acetylated low density lipoprotein in rats. Recognition by various receptors on Kupffer and endothelial liver cells. J Biol Chem. 1991;266:2282–9.PubMedGoogle Scholar
  42. 42.
    Tawara K, Ishihara M, Ogawa H, Tomikawa M. Effect of probucol, pantethine and their combinations on serum lipoprotein metabolism and on the incidence of atheromatous lesions in the rabbit. Jpn J Pharmcol. 1986;41:211–22.CrossRefGoogle Scholar
  43. 43.
    de Rijke YB, Hesseis EM, van Berkel TJC. Recognition sites on rat liver cells for oxidatively modified beta-very low density lipoproteins. Arterioscler Thromb. 1992;12:41–9.PubMedCrossRefGoogle Scholar
  44. 44.
    Seed M, Hoppichler F, Reaveley D, et al. Relation of serum lipoprotein(a) concentration and apolipoprotein(a) phenotype to coronary heart disease in patients with familial hypercholesterolemia. N Engl J Med. 1990;322:1494–9.PubMedCrossRefGoogle Scholar
  45. 45.
    de Rijke YB, Jürgens G, Hesseis EM, Hermann A, van Berkel TJC. In vivo fate and scavenger receptor recognition of oxidized lipoprotein[a] isoforms in rats. J Lipid Res. 1992;33:1315–25.PubMedGoogle Scholar
  46. 46.
    Pieters MN, Esbach S, Schouten D, Brouwer A, Knook DL, Van Berkel TJC. Cholesteryl esters from oxidized low-density lipoproteins are in vivo rapidly hydrolyzed in rat Kupffer cells and transported to liver parenchymal cells and bile. Hepatology. 1994;19:1459–67.PubMedGoogle Scholar
  47. 47.
    Sparrow CP, Parthasarathy S, Steinberg D. A macrophage receptor that recognizes oxidized low density lipoprotein but not acetylated low density lipoprotein. J Biol Chem. 1989;264:2599–604.PubMedGoogle Scholar
  48. 48.
    Arai H, Kita T, Yokode M, Narumiya S, Kawai C. Multiple receptors for modified low density lipoproteins in mouse peritoneal macrophages: different uptake mechanisms for acetylated and oxidized low density lipoproteins. Biochem Biophys Res Commun. 1989;159:1375–82.PubMedCrossRefGoogle Scholar
  49. 49.
    de Rijke YB, van Berkel TJC. Rat liver Kupffer and endothelial cells express different binding proteins for modified low density lipoproteins. Kupffer cells express a 95-kDa membrane protein as a specific binding site for oxidized low density lipoproteins. J Biol Chem. 1994;269:824–7.PubMedGoogle Scholar
  50. 50.
    Kodama T, Freeman M, Rohrer L, Zabrecky J, Matsudaira P, Krieger M. Type I macrophage scavenger receptor contains alpha-helical and collagen-like coiled coils. Nature. 1990;343:531–5.PubMedCrossRefGoogle Scholar
  51. 51.
    Ottnad E, Via DP, Frubis J, et al. Differentiation of binding sites on reconstituted hepatic scavenger receptors using oxidized low-density lipoprotein. Biochem J. 1992;281:745–51.PubMedGoogle Scholar
  52. 52.
    Stanton LW, White RT, Bryant CM, Protter AA, Endemann G. A macrophage Fc receptor for IgG is also a receptor for oxidized low density lipoprotein. J Biol Chem. 1992;267:22446–51.PubMedGoogle Scholar
  53. 53.
    Endemann G, Stanton LW, Madden KS, Bryant CM, White RT, Protter AA. CD36 is a receptor for oxidized low density lipoprotein. J Biol Chem. 1993;268:11811–16.PubMedGoogle Scholar
  54. 54.
    Krieger M, Acton S, Ashkenas J, Pearson A, Penman M, Resnick D. Molecular flypaper, host defense, and atherosclerosis. Structure, binding properties, and functions of macrophage scavenger receptors. J Biol Chem. 1993;268:4569–72.PubMedGoogle Scholar
  55. 55.
    Pearson AM, Rich A, Krieger M. Polynucleotide binding to macrophage scavenger receptors depends on the formation of base-quartet-stabilized four-stranded helices. J Biol Chem. 1993;268:3546–54.PubMedGoogle Scholar
  56. 56.
    Zhang H, Yang Y, Steinbrecher UP. Structural requirements for the binding of modified proteins to the scavenger receptor of macrophages. J Biol Chem. 1993;268:5535–42.PubMedGoogle Scholar
  57. 57.
    Resnick D, Freedman NJ, Xu S, Krieger M. Secreted extracellular domains of macrophage scavenger receptors form elongated trimers which specifically bind crocidolite asbestos. J Biol Chem. 1993;268:3538–45.PubMedGoogle Scholar
  58. 58.
    Acton S, Resnick D, Freeman M, Ekkel Y, Ashkenas J, Krieger M. The collagenous domains of macrophage scavenger receptors and complement component C1q mediate their similar, but not identical, binding specificities for polyanionic ligands. J Biol Chem. 1993;268:3530–7.PubMedGoogle Scholar
  59. 59.
    Ashkenas J, Penman M, Vasile E, Acton S, Freeman M, Krieger M. Structures and high and low affinity ligand binding properties of murine type I and type II macrophage scavenger receptors. J Lipid Res. 1993;34:983–1000.PubMedGoogle Scholar
  60. 60.
    Dejager S, Mietus-Synder M, Pitas RE. Oxidized low density lipoproteins bind to the scavenger receptor expressed by rabbit smooth muscle cells and macrophages. Arterioscler Thromb. 1993;13:371–8.PubMedCrossRefGoogle Scholar
  61. 61.
    Ueda Y, Arai H, Kawashima A, et al. Different expression of modified low density lipoprotein receptors in rabbit peritoneal macrophages and Kupffer cells. Atherosclerosis. 1993;101:25–35.PubMedCrossRefGoogle Scholar
  62. 62.
    Suzaki K, Kobori S, Ide M, et al. Acetyl-low density lipoprotein receptors on rat mesangial cells. Atherosclerosis. 1993;101:177–84.PubMedCrossRefGoogle Scholar
  63. 63.
    Miyazaki A, Sakai M, Yamaguchi E, Sakamoto Y, Shichiri M, Horiuchi S. Two independent macrophage receptors for acetylated high-density lipoprotein. Biochim Biophys Acta. 1993;1170:143–50.PubMedGoogle Scholar
  64. 64.
    Doi T, Higashino K, Kurihara Y, et al. Charged collagen structure mediates the recognition of negatively charged macromolecules by macrophage scavenger receptors. J Biol Chem. 1993;268:2126–33.PubMedGoogle Scholar
  65. 65.
    Miller GJ, Miller NE. Plasma-high-density-lipoprotein concentration and development of ischaemic heart-disease. Lancet. 1975;1:16–19.PubMedCrossRefGoogle Scholar
  66. 66.
    Glomset JA. The plasma lecithins: cholesterol acyltransferase reaction. J Lipid Res. 1968;9:155–67.PubMedGoogle Scholar
  67. 67.
    Badimon JJ, Badimon L, Galvez A, Dische R, Fuster V. High density lipoprotein plasma fractions inhibit aortic fatty streaks in cholesterol-fed rabbits. Lab Invest. 1989;60:455–61.PubMedGoogle Scholar
  68. 68.
    Badimon JJ, Badimon L, Fuster V. Regression of atherosclerotic lesions by high density lipoprotein plasma fraction in the cholesterol-fed rabbit. J Clin Invest. 1990;85:1234–41.PubMedCrossRefGoogle Scholar
  69. 69.
    Walsh A, Ito Y, Breslow JL. High levels of human apolipoprotein A-I in transgenic mice result in increased plasma levels of small high density lipoprotein (HDL) particles comparable to human HDL3. J Biol Chem. 1989;264:6488–94.PubMedGoogle Scholar
  70. 70.
    Rubin EM, Ishida BY, Clift SM, Krauss RM. Expression of human apolipoprotein A-I in transgenic mice results in reduced plasma levels of murine apolipoprotein A-I and the appearance of two new high density lipoprotein size subclasses. Proc Natl Acad Sci USA. 1991;88:434–8.PubMedCrossRefGoogle Scholar
  71. 71.
    Brinton EA, Eisenberg S, Breslow JL. Elevated high density lipoprotein cholesterol levels correlate with decreased apolipoprotein A-I and A-II fractional catabolic rate in women. J Clin Invest. 1989;84:262–9.PubMedCrossRefGoogle Scholar
  72. 72.
    Rubin EM, Krauss RM, Spangler EA, Verstuyft JG, Clift SM. Inhibition of early atherogenesis in transgenic mice by human apolipoprotein AI. Nature. 1991;353:265–7.PubMedCrossRefGoogle Scholar
  73. 73.
    Aalto-Setäla K. European Vascular Biology Association Meeting, March 23–27 1993, Tampere, Finland.Google Scholar
  74. 74.
    Schwartz CC, Halloran LG, Vlahcevic ZR, Gregory DH, Swell L. Preferential utilization of free cholesterol from high-density lipoproteins for biliary cholesterol secretion in man. Science. 1978;200:62–4.PubMedCrossRefGoogle Scholar
  75. 75.
    Pieters MN, Schouten D, Bakkeren HF, et al. Selective uptake of cholesteryl esters from apolipoprotein-E-free high-density lipoproteins by rat parenchymal cells in vivo is efficiently coupled to bile acid synthesis. Biochem J. 1991;280:359–65.PubMedGoogle Scholar
  76. 76.
    Bakkeren HF, Kuipers F, Vonk RJ, Van Berkel TJC. Evidence for reverse cholesterol transport in vivo from liver endothelial cells to parenchymal cells and bile by high-density lipoprotein. Biochem J. 1990;268:685–91.PubMedGoogle Scholar

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© Kluwer Academic Publishers 1996

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  • T. J. C. Van Berkel

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