Journal of Molecular Medicine

, Volume 83, Issue 5, pp 329–342 | Cite as

The key role of apolipoprotein E in atherosclerosis

  • Kirsty Greenow
  • Nigel J. Pearce
  • Dipak P. RamjiEmail author


Apolipoprotein E is a multifunctional protein that is synthesized by the liver and several peripheral tissues and cell types, including macrophages. The protein is involved in the efficient hepatic uptake of lipoprotein particles, stimulation of cholesterol efflux from macrophage foam cells in the atherosclerotic lesion, and the regulation of immune and inflammatory responses. Apolipoprotein E deficiency in mice leads to the development of atherosclerosis and re-expression of the protein reduces the extent of the disease. This review presents evidence for the potent anti-atherogenic action of apolipoprotein E and describes our current understanding of its multiple functions and regulation by factors implicated in the pathogenesis of cardiovascular disease


Atherosclerosis Lipid metabolism Lipoproteins Macrophages Reverse cholesterol transport 



ATP-binding cassette transporter A1


Alzheimer’s disease




ApoE receptor 2


Hepatic control regions


High density lipoproteins


Heparan-sulphate proteoglycans


Low-density lipoproteins


LDL receptor


LDL receptor-related protein




Smooth muscle cells


Very low density lipoproteins



We thank the British Heart Foundation for financial support, and apologize to all those authors whose work could not be cited because of space limitations.


  1. 1.
    Ross R (1999) Atherosclerosis-an anti-inflammatory disease N Engl J Med 340:115–126Google Scholar
  2. 2.
    Shore B, Shore VG (1973) Heterogeneity of human plasma very low density lipoproteins. Separation of species differing in protein components. Biochemistry 12:502–507Google Scholar
  3. 3.
    Allan CM, Walker D, Segrest JP, Taylor JM (1995) Identification of a new human gene (APOC4) in the apolipoprotein E, C-I, and C-II gene locus. Genomics 28:291–300CrossRefGoogle Scholar
  4. 4.
    Zannis V, McPherson J, Goldberger G, Karathanasis SK, Breslow JL (1984) Synthesis, intracellular processing, and signal peptide of human apolipoprotein E. J Biol Chem 259:5495–5499Google Scholar
  5. 5.
    Mazzone T, Papagiannes E, Magner J (1986) Early kinetics of human macrophage apolipoprotein E synthesis and incorporation of carbohydrate precursors. Biochim Biophys Acta 875:393–396Google Scholar
  6. 6.
    Mazzone T, Pustelnikas L, Reardon C (1992) Post-translational regulation of macrophage apoprotein E production. J Biol Chem 267:1081–1087Google Scholar
  7. 7.
    Duan HW, Lin CY, Mazzone T (1997) Degradation of macrophage apoE in nonlysosomal compartment. J Biol Chem 272:31156–31162CrossRefGoogle Scholar
  8. 8.
    Lucas M, Mazzone T (1996) Cell surface proteoglycans modulate net synthesis and secretion of macrophage apolipoprotein E. J Biol Chem 271:13454–13460CrossRefGoogle Scholar
  9. 9.
    Zhao Y, Mazzone T (2000) Transport and processing of endogenously synthesised apoE on the macrophage cell surface. J Biol Chem 275:4759–4765CrossRefGoogle Scholar
  10. 10.
    Heeren J, Weber W, Beisiegel U (1999) Intracellular processing of endocytosed triglyceride-rich lipoproteins comprises both recycling and degradation. J Cell Sci 112:349–359Google Scholar
  11. 11.
    Heeren J, Grewal T, Jackle S, Beisiegel U (2001) Recycling of apolipoprotein E and lipoprotein lipase through endosomal compartments in vivo. J Biol Chem 276:42333–42338CrossRefGoogle Scholar
  12. 12.
    Heeren J, Grewal T, Laatsch A, Rottke D, Rinninger F, Enrich C, Beisiegel U (2003) Recycling of apolipoprotein E is associated with cholesterol efflux and high density lipoprotein internalization. J Biol Chem 278:14370–14378CrossRefGoogle Scholar
  13. 13.
    Duan H, Gu D, Mazzone T (2000) Sterols and inhibitors of sterol transport modulates the degradation and secretion of macrophage apoE: requirement for the C-terminal domain. Biochim Biophys Acta 1484:142–150Google Scholar
  14. 14.
    Mazzone T (1996) Apolipoprotein E secretion by macrophages: its potential physiological functions. Curr Opin Lipidol 7:303–307Google Scholar
  15. 15.
    Elshourbagy NA, Liao WS, Mahley, RW, Taylor JM (1985) Apolipoprotein E mRNA is abundant in the brain and adrenals, as well as in the liver, and is present in other peripheral tissues of rats and marmosets. Proc Natl Acad Sci USA 82:203–207Google Scholar
  16. 16.
    Newman T, Dawson P, Rudel LL, Williams DL (1985) Quantitation of apolipoprotein E mRNA in the liver and peripheral tissues of non-human primates. J Biol Chem 260:2452–2457Google Scholar
  17. 17.
    Weisgraber KH (1994) Apolipoprotein E: structure-function relationships. Adv Protein Chem 45:249–302PubMedGoogle Scholar
  18. 18.
    Wilson C, Wardell MR, Weisgraber KH, Mahley RW, Agard DA (1991) Three-dimensional structure of the LDL receptor-binding domain of human apolipoprotein E. Science 252:1817–1822Google Scholar
  19. 19.
    Lalazar A, Mahley RW (1989) Human apolipoprotein E. Receptor binding activity of truncated variants with carboxyl-terminal deletions. J Biol Chem 264:8447–8450Google Scholar
  20. 20.
    Lund-Katz S, Zaiou M, Wehrli S, Dhanasekaran P, Baldwin F, Weisgraber KH, Phillips MC (2000) Effects of lipid interaction on the lysine microenvironments in apolipoprotein E. J Biol Chem 275:34459–34464CrossRefGoogle Scholar
  21. 21.
    Raussens V, Slupsky CM, Sykes BD, Ryan RO (2003) Lipid-bound structure of an apolipoprotein E-derived peptide. J Biol Chem 278:25998–26006CrossRefGoogle Scholar
  22. 22.
    Saito H, Lund-Katz S, Phillips MC (2004) Contributions of domain structure and lipid interaction to the functionality of exchangeable human apolipoproteins. Prog Lipid Res 43:350–380CrossRefGoogle Scholar
  23. 23.
    Weisgraber KH, Rall SC Jr, Mahley RW, Milne RW, Marcel YL, Sparrow JT (1986) Human apolipoprotein E. Determination of the heparin binding sites of apolipoprotein E3. J Biol Chem 261:2068–2076Google Scholar
  24. 24.
    Libeu CP, Lund-Katz S, Phillips MC, Wehrli S, Hernaiz MJ, Capila I, Linhardt RJ, Raffai RL, Newhouse YM, Zhou F, Weisgraber KH (2001) New insights into the heparan sulfate proteoglycan-binding activity of apolipoprotein E. J Biol Chem 276:39138–39144CrossRefGoogle Scholar
  25. 25.
    Li X, Kan HY, Lavrentiadou S, Krieger M, Zannis V (2002) Reconstituted discoidal ApoE-phospholipid particles are ligands for the scavenger receptor BI. The amino-terminal 1–165 domain of ApoE suffices for receptor binding. J Biol Chem 277:21149–21157CrossRefGoogle Scholar
  26. 26.
    Thuahnai ST, Lund-Katz S, Anantharamaiah GM, Williams DL, Phillips MC (2003) A quantitative analysis of apolipoprotein binding to SR-BI: multiple binding sites for lipid-free and lipid-associated apolipoproteins. J Lipid Res 44:1132–1142CrossRefGoogle Scholar
  27. 27.
    Choy N, Raussens V, Narayanaswami V (2003) Inter-molecular coiled-coil formation in human apolipoprotein E C-terminal domain. J Mol Biol 334:527–539CrossRefGoogle Scholar
  28. 28.
    Rall SC Jr, Mahley RW (1992) The role of apolipoprotein E genetic variants in lipoprotein disorders. J Intern Med 231:653–659Google Scholar
  29. 29.
    Richard P, Beucler I, Pascual De Zulueta M, Biteau N, De Gennes JL, Iron A (1997) Compound heterozygote for both rare apolipoprotein E1 (Gly127→Asp, Arg158→Cys) and E3 (Cys112→Arg, Arg251→Gly) alleles in a multigeneration pedigree with hyperlipoproteinaemia. Clin Sci (Lond) 93:89–95Google Scholar
  30. 30.
    Hoffer MJ, Niththyananthan S, Naoumova RP, Hibirige MS, Frants RR, Havekes LM, Thompson GR (1996) Apolipoprotein E1-Hammersmith (Lys146→Asn; Arg147→Trp), due to a dinucleotide substitution, is associated with early manifestation of dominant type III hyperlipoproteinaemia. Atherosclerosis 124:183–189CrossRefGoogle Scholar
  31. 31.
    Hoffmann MM, Scharnagi H, Koster W, Winkler K, Wieland H, Marz W (2001) Apolipoprotein E1 Baden (Arg180→Cys). A new apolipoprotein E variant associated with hypertriglyceridemia. Clin Chim Acta 303:41–48CrossRefGoogle Scholar
  32. 32.
    van den Maagdenberg AM, Weng W, de Bruijn IH, de Knijh P, Funke H, Smelt AH, Gevers Leuven JA, van’t Hooft FM, Assmann G, Hofker MH et al (1993) Characterization of five new mutants in the carboxyl-terminal domain of human apolipoprotein E: no cosegregation with severe hyperlipidemia. Am J Hum Genet 52:937–946Google Scholar
  33. 33.
    Walden CC, Huff MW, Leiter LA, Connelly PW, Hegele RA (1994) Detection of a new apolipoprotein-E mutation in type III hyperlipidemia using deoxyribonucleic acid restriction isotyping. J Clin Endocrinol Metab 78:699–704Google Scholar
  34. 34.
    Rolleri M, Vivona N, Emmanuele G, Cefalu AB, Pisciotta L, Guido V, Noto D, Fiore B, Barbagallo CM, Notarbartolo A, Travali S, Bertolini S, Averna MR (2003) Two italian kindreds carrying the Arg136→Ser mutation of the ApoE gene: development of premature and severe atherosclerosis in the presence of epsilon 2 as second allele. Nutr Metab Cardiovasc Dis 13:93–99Google Scholar
  35. 35.
    Feussner G, Albanese M, Mann WA, Valencia A, Schuster H (1996) Apolipoprotein E2 (Arg136→Cys), a variant of apolipoprotein E associated with late-onset dominance of type III hyperlipoproteinaemia. Eur J Clin Invest 26:13–23CrossRefGoogle Scholar
  36. 36.
    Richard P, de Zulueta MP, Beucler I, De Gennes JL, Cassaigne A, Iron A (1995) Identification of a new apolipoprotein E variant (E2 Arg142→Leu) in type III hyperlipidemia. Atherosclerosis 112:19–28CrossRefGoogle Scholar
  37. 37.
    Hoffmann M, Scharnagi H, Panagiotou E, Banghard W, Wieland H, Marz W (2002) Diminished LDL receptor and high heparin binding of apolipoprotein E2 Sendai associated with lipoprotein glomerulopathy. J Am Soc Nephrol 12:524–530Google Scholar
  38. 38.
    Vialettes B, Reynier P, Atlan-Gepner C, Mekki N, Lesluyes-Mazzochi L, Luc G, Lairon D, Malthiery Y (2000) Dietary fat clearance in type V hyperlipoproteinaemia secondary to a rare variant of human apolipoprotein E: the apolipoprotein E3 (Arg136→Ser). Br J Nutr 83:615–622Google Scholar
  39. 39.
    Hidaka H, Tozuka M, Hidaka E, Yamauchi K, Ota H, Honda T, Katsuyama T (2001) Characterization of an apolipoprotein E3 variant (Arg145→His) associated with mild hypertriglyceridemia. Ann Clin Lab Sci 31:163–170Google Scholar
  40. 40.
    Minnich A, Weisgraber KH, Newhouse Y, Dong LM, Fortin LJ, Tremblay M, Davignon J (1995) Identification and characterization of a novel apolipoprotein E variant, apolipoprotein E3’(Arg136→His): association with mild dyslipidemia and double pre-beta very low density lipoproteins. J Lipid Res 36:57–66Google Scholar
  41. 41.
    Lohse P, Rader DJ, Brewer HB Jr (1992) Heterozygosity for apolipoprotein E-4Philadelphia (Glu13→Lys, Arg145→Cys) is associated with incomplete dominance of type III hyperlipoproteinemia. J Biol Chem 267:13642–13646Google Scholar
  42. 42.
    Orth M, Weng W, Funke H, Steinmetz A, Assmann G, Nauck M, Dierkes J, Ambrosch A, Weisgraber KH, Mahley RW, Wieland H, Luley C (1999) Effects of a frequent apolipoprotein E isoform, ApoE4Freiburg (Leu28→Pro), on lipoproteins and the prevalence of coronary artery disease in whites. Arterioscler Thromb Vasc Biol 19:1306–1315Google Scholar
  43. 43.
    Wardell MR, Rall SC Jr, Schaefer EJ, Kane JP, Weisgraber KH (1991) Two apolipoprotein E5 variants illustrate the importance of the position of additional positive charge on receptor-binding activity. J Lipid Res 32:521–528Google Scholar
  44. 44.
    Mailly F, Xu CF, Xhignesse M, Lussier-Cacan S, Talmud PJ, Davignon J, Humphries SE, Nestruck AC (1991) Characterization of a new apolipoprotein E5 variant detected in two French-Canadian subjects. J Lipid Res 32:613–620Google Scholar
  45. 45.
    Scacchi R, De Stefano GF, Ruggeri M, Corbo RM (2003) Genetic variation at apolipoprotein E locus in Ethopia: an E5 variant corresponds to two different mutant alleles: E*5 (Glu212Lys) and E*5 (Gln202Lys; Cys112Arg). Hum Biol 75:293–300Google Scholar
  46. 46.
    Feussner G, Scharnagl H, Scherbaum C, Acac J, Dobmeyer J, Lohrmann J, Wieland H, Marz W (1996) Apolipoprotein E5 (Glu212→Lys): increased binding to cell surface proteoglycans but decreased uptake and lysosomal degradation in cultured fibroblasts. J Lipid Res 37:1632–1645Google Scholar
  47. 47.
    Yanagi K, Yamashita S, Hiraoka H, Ishigami M, Kihara S, Hirano K, Sakai N, Nozaki S, Funahashi T, Kameda-Takemura K, Kubo M, Tokunaga K, Matsuzawa Y (1997) Increased serum remnant lipoproteins in patients with apolipoprotein E7 (apoE Suita). Atherosclerosis 131:49–58CrossRefGoogle Scholar
  48. 48.
    Eichner JE, Dunn ST, Perveen G, Thompson DM, Stewart KE, Stroehla BC (2002) Apolipoprotein E polymorphism and cardiovascuar disease: a HuGE review. Am J Epidemiol 155:487–495CrossRefGoogle Scholar
  49. 49.
    Wernette-Hammond ME, Lauer SJ, Corsini A, Walker D, Taylor JM, Rall SC Jr (1989) Glycosylation of human apolipoprotein E: the carbohydrate attachment site is threonine 194. J Biol Chem 264:9094–9101Google Scholar
  50. 50.
    Zanni EE, Kouvatsi A, Hadzopoulou-Cladaras M, Krieger M, Zannis VI (1989) Expression of ApoE gene in Chinese hamster cells with a reversible defect in O-glycosylation. Glycosylation is not required for apoE secretion. J Biol Chem 264:9137–9140Google Scholar
  51. 51.
    Morrow JA, Segall ML, Lund-Katz S, Phillips MC, Knapp M, Rupp B, Weisgraber KH (2000) Differences in stability among the human apolipoprotein E isoforms determined by the amino-terminal domain. Biochemistry 39:11657–11666CrossRefGoogle Scholar
  52. 52.
    Acharya P, Segall ML, Zaiou M, Morrow J, Weisgraber KH, Phillips MC, Lund-Katz S, Snow J (2002) Comparison of the stabilities and unfolding pathways of human apolipoprotein E isoforms by differential scanning calorimetry and circular dichroism. Biochim Biophys Acta 1584:9–19Google Scholar
  53. 53.
    Innerarity TL, Weisgraber KH, Arnold KS, Rall SC Jr, Mahley RW (1984) Normalization of receptor binding of apolipoprotein E2. Evidence for modulation of the binding site conformation. J Biol Chem 259:7261–7267Google Scholar
  54. 54.
    Lalazar A, Weisgraber KH, Rall SC Jr, Giladi H, Innerarity TL, Levanon AZ, Boyles JK, Amit B, Gorecki M, Mahley RW, Vogel T (1988) Site-specific mutagenesis of human apolipoprotein E. Receptor binding activity of variants with single amino acid substitutions. J Biol Chem 263:3542–3545Google Scholar
  55. 55.
    Dong L-M, Weisgraber KH (1996) Human apolipoprotein E4 domain interaction. J Biol Chem 271:19053–19057CrossRefGoogle Scholar
  56. 56.
    Saito H, Dhanasekaran P, Baldwin F, Weisgraber KH, Phillips MC, Lund-Katz S (2003) Effects of polymorphism on the lipid interaction of human apolipoprotein E. J Biol Chem 278:40723–40729CrossRefGoogle Scholar
  57. 57.
    Mahley RW, Rall SC Jr (2000) Apolipoprotein E: far more than a lipid transport protein. Annu Rev Genomics Hum Genet 1:507–537CrossRefGoogle Scholar
  58. 58.
    Gregg RE, Zech LA, Schaefer EJ, Stark D, Wilson D, Brewer HB Jr (1986) Abnormal in vivo metabolism of apolipoprotein E4 in humans. J Clin Invest 78:815–821Google Scholar
  59. 59.
    Weintraub MS, Eisenberg S, Breslow JL (1987) Dietary fat clearance in normal subjects is regulated by genetic variation in apolipoprotein E. J Clin Invest 80:1571–1577Google Scholar
  60. 60.
    Mahley RW, Huang Y, Rall SC Jr (1999) Pathogenesis of type III hyperlipoproteinemia (dysbetalipoproteinemia): questions, quandaries and paradoxes. J Lipid Res 40:1933–1949Google Scholar
  61. 61.
    Song Y, Stampfer MJ, Liu S (2004) Meta-analysis: apolipoprotein E genotypes and risk for coronary heart disease. Ann Intern Med 141:137–147Google Scholar
  62. 62.
    Kolovou G, Daskalova D, Mikhailidis DP (2003) Apolipoprotein E polymorphism and atherosclerosis. Angiology 54:59–71Google Scholar
  63. 63.
    Stengard JH, Weiss KM, Sing CF (1998) An ecological study of association between coronary heart disease mortality rates in men and the relative frequencies of common allelic variations in the gene coding for apolipoprotein E. Hum Genet 103:234–241CrossRefGoogle Scholar
  64. 64.
    Eichner JE, Kuller LH, Orchard TJ, Grandits GA, McCallum LM, Ferrell RE, Neaton JD (1993) Relation of apolipoprotein E phenotype to myocardial infarction and mortality from coronary artery disease. Am J Cardiol 71:160–165Google Scholar
  65. 65.
    Wang XL, McCredie RM, Wilcken DEL (1995) Polymorphisms of the apolipoprotein E gene and severity of coronary artery disease defined by angiography. Arterioscler Thromb Vasc Biol 15:1030–1034Google Scholar
  66. 66.
    Wilson PW, Schaefer EJ, Larson MG, Ordovas JM (1996) Apolipoprotein E alleles and risk of coronary disease, a meta-analysis. Arterioscler Thromb Vasc Biol 16:1250–1255Google Scholar
  67. 67.
    Humphries SE, Talmud PJ, Hawe E, Bolla M, Day INM, MillerGJ (2001) Apolipoprotein E4 and coronary heart disease in middle-aged men who smoke: a prospective study. Lancet 358:115–119CrossRefGoogle Scholar
  68. 68.
    Karvonen J, Kauma H, Kervinen K, Ukkola O, Rantala M, Paivansalo M, Savolainen MJ, Kesaniemi YA (2002) Apolipoprotein E polymorphism affects carotid artery atherosclerosis in smoking hypertensive men. J Hypertens 20:2371–2378CrossRefGoogle Scholar
  69. 69.
    Talmud PJ, Lewis SJ, Hawe E, Martin S, Acharya J, Marmot MG, Humphries SE, Brunner EJ (2004) Atherosclerosis 177:105–112CrossRefGoogle Scholar
  70. 70.
    Raber J, Huang Y, Ashford JW (2004) ApoE genotype accounts for the vast majority of AD risk and AD pathology. Neurobiol Aging 25:641–650CrossRefGoogle Scholar
  71. 71.
    Lahiri DK, Sambamurti K, Bennet DA (2004) Apolipoprotein gene and its interaction with the environmentally driven risk factors: molecular, genetic and epidemiological studies of Alzheimer’s disease. Neurobiol Aging 25:651–660CrossRefGoogle Scholar
  72. 72.
    Holtzman DM, Bales KR, Tenkova T, Fagan AM, Parsadanian M, Sartorius LJ, Mackey B, Olney J, McKeel D, Wozniak D, Paul SM (2000) Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 97:2892–2897CrossRefGoogle Scholar
  73. 73.
    Herz J, Beffert U (2000) Apolipoprotein E receptors: linking brain development and Alzheimer’s disease. Nat Rev Neurosci 1:51–58CrossRefGoogle Scholar
  74. 74.
    Ordovas JM, Schaefer EJ (2000) Genetic determinants of plasma lipid response to dietary intervention: the role of the APOA1/C3/A4 gene cluster and the APOE gene. Br J Nutr 83:S127–S136Google Scholar
  75. 75.
    Schaefer EJ, Lamon-Fava S, Johnson S, Ordovas JM, Schaefer MM, Castelli WP, Wilson PW (1994) Effects of gender and menopausal status on the association of apolipoprotein E phenotype with plasma lipoprotein levels. Results from the Framingham Offspring Study. Arterioscler Thromb 14:1105–1113Google Scholar
  76. 76.
    Marques-Vidal P, Bongard V, Ruidavets JB, Fauvel J, Hanaire-Broutin H, Perret B, Ferrieres J (2003) Obesity and alcohol modulate the effect of apolipoprotein E polymorphism on lipids and insulin. Obes Res 11:1200–1206Google Scholar
  77. 77.
    Ordovas JM (2001) Genetics, postprandial lipemia and obesity. Nutr Metab Cardiovasc Dis 11:118–133Google Scholar
  78. 78.
    Gerdes LU, Gerdes C, Kervinen K, Savolainen M, Klausen IC, Hansen PS, Kesaniemi YA, Faergeman O (2000) The apolipoprotein epsilon4 allele determines prognosis and the effect on prognosis of simvastatin in survivors of myocardial infarction: a substudy of the Scandinavian simvastatin survival study. Circulation 101:1366–1371Google Scholar
  79. 79.
    Ordovas JM, Lopez-Miranda J, Perez-Jimenez F, Rodriguez C, Park J-S, Cole T, Schaefer EJ (1995) Effect of apolipoprotein E and A-IV phenotypes on the low density lipoprotein response to HMGCoA reductase inhibitor therapy. Atherosclerosis 113:157–166CrossRefGoogle Scholar
  80. 80.
    Sanllehy C, Casals E, Rodriguez-Villar C, Zambon D, Ojuel J, Ballesta AM, Ros E (1998) Lack of interaction of apolipoprotein E phenotype with the lipoprotein response to lovastatin or gemfibrozil in patients with primary hypercholesterolemia. Metabolism 47:560–565CrossRefGoogle Scholar
  81. 81.
    Pena R, Lahoz C, Mostaza JM, Jimenez J, Subirats E, Pinto X, Taboada M, Lopez-Pastor A, Rap Study Group (2002) Effect of apoE genotype on the hypolipidaemic response to pravastatin in an outpatient setting. J Intern Med 251:518–525CrossRefGoogle Scholar
  82. 82.
    Maitland-van der Zee AH, Stricker BH, Klungel OH, Kastelein JJ, Hofman A, Witteman JC, Breteler MM, Leufkens HG, van Duijn CM, de Boer A (2002) The effectiveness of hydroxy-methylglutaryl coenzyme A reductase inhibitors (statins) in the elderly is not influenced by apolipoprotein E genotype. Pharmacogenetics 12:647–653CrossRefGoogle Scholar
  83. 83.
    Batalla A, Alvarez R, Reguero JR, Hevia S, Iglesias-Cubero G, Alvarez V, Corhna A, Gonzalez P, Celada MM, Medina A, Coto E (2000) Synergistic effect between apolipoprotein E and angiotensinogen gene polymorphisms in the risk for early myocardial infarction. Clin Chem 46:1910–1915Google Scholar
  84. 84.
    Tai ES, Demissie S, Cupples LA, Corella D, Wilson PW, Schaefer EJ, Ordovas JM (2002) Association between the PPARA L162 V polymorphism and plasma lipid levels: the Framingham Offspring Study. Arterioscler Thromb Vasc Biol 22:805–810CrossRefPubMedGoogle Scholar
  85. 85.
    Schaefer E, Gregg R, Ghiselli G, Forte TM, Ordovas JM, Zech LA, Brewer HB Jr (1986) Familial apolipoprotein E deficiency. J Clin Invest 78:1206–1219Google Scholar
  86. 86.
    Ghiselli G, Schaefer EJ, Gascon P, Brewer HB Jr (1981) Type III hyperlipoproteinemia associated with apolipoprotein E deficiency. Science 214:1239–1241Google Scholar
  87. 87.
    Plump AS, Smith JD, Hayek T, Aalto-Setala K, Walsh A, Verstuyft JG, Rubin EM, Breslow JL (1992) Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell 71:343–353CrossRefGoogle Scholar
  88. 88.
    Zhang SH, Reddick RL, Piedrahita JA, Maeda N (1992) Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science 258:468–472Google Scholar
  89. 89.
    Zhang SH, Reddick RL, Burkey B, Maeda N (1994) Diet-induced atherosclerosis in mice heterozygous and homozygous for apolipoprotein E gene disruption. J Clin Invest 94:937–945Google Scholar
  90. 90.
    Tsukamoto K, Tangirala R, Chun SH, Pure E, Rader DJ (1999) Rapid regression of atherosclerosis induced by liver-directed gene transfer of ApoE in ApoE-deficient mice. Arterioscler Thromb Vasc Biol 19:2162–2170Google Scholar
  91. 91.
    Desurmont C, Caillund JM, Emmanuel F, Benoit P, Fruchart JC, Castro G, Branelle CD, Heard JM, Duverger N (2000) Complete atherosclerosis regression after human apoE gene transfer in apoE-deficient/nude mice. Arterioscler Thromb Vasc Biol 20:435–442Google Scholar
  92. 92.
    Shimano H, Yamada N, Katsuki M, Shimada M, Gotoda T, Harada K, Murase T, Fukazawa C, Takaku F, Yazaki Y (1992) Overexpression of apolipoprotein E in transgenic mice: marked reduction in plasma lipoproteins except high density lipoprotein and resistance against diet-induced hypercholesterolemia. Proc Natl Acad Sci U S A 89:1750–1754Google Scholar
  93. 93.
    Nikoulin IR, Curtiss LK (1998) An apolipoprotein synthetic peptide targets to lipoproteins in plasma and mediates both cellular lipoprotein interactions in vitro and acute clearance of cholesterol-rich lipoproteins in vivo. J Clin Invest 101:223–234Google Scholar
  94. 94.
    Rosenfeld ME, Butler S, Ord VA, Lipton BA, Dyer CA, Curtiss LK, Polinski W, Witztum JL (1993) Abundant expression of apolipoprotein E by macrophages in human and rabbit atherosclerotic lesions, Arterioscler Thromb 13:1382–1389Google Scholar
  95. 95.
    Fazio S, Babaev VR, Murray AB, Hasty AH, Carter KJ, Gleaves LA, Atkinson JB, Linton MF (1997) Increased atherosclerosis in mice reconstituted with apolipoprotein E null macrophages. Proc Natl Acad Sci USA 94:4647–4652CrossRefGoogle Scholar
  96. 96.
    Boisvert WA, Curtiss LK (1999) Elimination of macrophage-specific apolipoprotein E reduces diet-induced atherosclerosis in C57BL/6 J male mice. J Lipid Res 40:806–813Google Scholar
  97. 97.
    Van Eck M, Herijgers N, Vidgeon-Hart M, Pearce NJ, Hoogerbrugge PM, Groot PH, Van Berkel TJ (2000) Accelerated atherosclerosis in C57BL/6 mice transplanted with ApoE-deficient bone marrow. Atherosclerosis 150:71–80CrossRefGoogle Scholar
  98. 98.
    Shimano H, Ohsuga J, Shimanda M, Kawamura M, Gotoda T, Harada K, Ohsuga J, Yazaki Y, Yamada N (1995) Inhibition of diet-induced atheroma formation in transgenic mice expressing apolipoprotein E in the arterial wall. J Clin Invest 95:469–476Google Scholar
  99. 99.
    Bellosta S, Mahley RW, Sanan, DA, Murata J, Newland DL, Taylor JM, Pitas RE (1995) Macrophage-specific expression of human apolipoprotein E reduces atherosclerosis in hypercholesterolemic apolipoprotein E-null mice. J Clin Invest 96:2170–2179Google Scholar
  100. 100.
    Hasty AH, Linton MF, Brandt SJ, Babaev VR, Gleaves LA, Fazio S (1999) Retroviral gene therapy in apoE-deficient mice: apoE expression in the artery wall reduces early foam cell lesion formation. Circulation 99:2571–2576Google Scholar
  101. 101.
    Gough PJ, Raines EW (2003) Gene therapy of apolipoprotein E-deficient mice using a novel macrophage-specific retroviral vector. Blood 101:485–491CrossRefGoogle Scholar
  102. 102.
    Linton MF, Atkinson JB, Fazio S (1995) Prevention of atherosclerosis in apolipoprotein E-deficient mice by bone marrow transplantation. Science 267:1034–1037Google Scholar
  103. 103.
    Van Eck M, Herijgers N, Yates J, Pearce NJ, Hoogerbrugge PM, Groot PH, Van Berkel TJ (1997) Bone marrow transplantation in apolipoprotein E-deficient mice: effect of apoE gene dosage on serum lipid concentrations (beta) VLDL catabolism, and atherosclerosis. Arterioscler Thromb Vasc Biol 17:3117–3126Google Scholar
  104. 104.
    Mahley RW, Ji ZS (1999) Remnant lipoprotein metabolism: key pathway involving cell-surface heparan sulfate proteoglycans and apolipoprotein E. J Lipid Res 40:1–16Google Scholar
  105. 105.
    Linton MF, Hasty AH, Babaev VR, Fazio S (1998) Hepatic apoE expression is required for remnant lipoprotein clearance in the absence of the low density lipoprotein receptor. J Clin Invest 101:1726–1736Google Scholar
  106. 106.
    Kuipers F, Jong MC, Lin Y, Eck M, Havinga R, Bloks V, Verkade HJ, Hofker MH, Moshage H, Berkel TJ, Vonk RJ, Havekes LM (1997) Impaired secretion of very low density lipoprotein-triglycerides by apolipoprotein E-deficient mouse hepatocytes. J Clin Invest 100:2915–2922Google Scholar
  107. 107.
    Huang Y, Li XG, Rall SC, Taylor JM, Von Eckardstein A, Assmann G, Mahley RW (1998) Overexpression and accumulation of apolipoprotein E as a cause of hypertriglyceridemia. J Biol Chem 273:26388–26393CrossRefGoogle Scholar
  108. 108.
    Thuren T, Weisgraber KH, Sisson P, Waite M (1992) Role of apolipoprotein E in hepatic lipase catalysed hydrolysis of phospholipid in high density lipoproteins. Biochemistry 31:2332–2338Google Scholar
  109. 109.
    Kinoshita M, Arai H, Fukasawa M, Watanabe T, Tsukamoto K, Hashimoto Y, Inoue K, Kurokawa K, Teramoto T (1993) Apolipoprotein E enhances lipid exchange between lipoproteins mediated by cholesteryl ester transfer protein. J Lipid Res 34:261–268Google Scholar
  110. 110.
    De Pauw M, Vanloo B, Weisgraber K, Rosseneu M (1995) Comparison of lipid-binding and lecithin: cholesterol acyltransferase activation of the amino- and carboxyl-terminal domains of human apolipoprotein E3. Biochemistry 34:10953–10966Google Scholar
  111. 111.
    Dory L (1991) Regulation of apolipoprotein E secretion by high-density lipoprotein3 in mouse macrophages. J Lipid Res 32:783–792Google Scholar
  112. 112.
    Hayek T, Oiknine J, Brook JG, Aviram M (1994) Role of HDL apolipoprotein E in cellular cholesterol efflux. Studies in apoE knockout transgenic mice. Biochem Biophys Res Commun 205:1072–1078CrossRefGoogle Scholar
  113. 113.
    Cullen P, Cignarella A, Brennhausen B, Mohr S, Assmann G, Von Eckardstein A (1998) Phenotype-dependant differences in apoE metabolism and in cholesterol homeostasis in human monocyte-derived macrophages. J Clin Invest 101:1670–1677Google Scholar
  114. 114.
    Mazzone T, Reardon C (1994) Expression of heterologous human apolipoprotein E by J774 macrophages enhances cholesterol efflux to HDL3. J Lipid Res 35:1345–1353Google Scholar
  115. 115.
    Smith JD, Miyata M, Ginsberg M, Grigaux C, Shmookler E, Plump AS (1996) Cyclic AMP induces apolipoprotein E binding activity and promotes cholesterol efflux from a macrophage cell line to apolipoprotein receptors. J Biol Chem 271:30647–30655CrossRefGoogle Scholar
  116. 116.
    Lin C-Y, Lucas M, Mazzone T (1998) Endogenous apoE expression modulates HDL3 binding to macrophages. J Lipid Res 39:293–301Google Scholar
  117. 117.
    Lin, C-Y, Huang Z-H, Mazzone T (2001) Interaction with proteoglycans enhances the sterol efflux produced by endogenous expression of macrophage apoE. J Lipid Res 42:1125–1133Google Scholar
  118. 118.
    Krieger M (1999) Charting the fate of the “good cholesterol”: identification and characterisation of the high-density lipoprotein receptor SR-BI. Annu Rev Biochem 68:523–558CrossRefGoogle Scholar
  119. 119.
    Krimbou L, Denis M, Haidar B, Carrier M, Marcil M, Genest J Jr (2004) Molecular interactions between apoE and ABCA1: impact on apoE lipidation. J Lipid Res 45:839–848CrossRefGoogle Scholar
  120. 120.
    Thorngate FE, Yancey PG, Kellner-Weibel G, Rudel LL, Rothblat GH, Williams DL (2003) Testing the role of apoA-I, HDL, and cholesterol efflux in the atheroprotective action of low-level apoE expression. J Lipid Res 44:2331–2338CrossRefGoogle Scholar
  121. 121.
    Thorngate FE, Rudel LL, Walzem RL, Williams DL (2000) Low levels of extrahepatic nonmacrophage apoE inhibit atherosclerosis without correcting hypercholesterolemia in apoE-deficient mice. Arterioscler Thromb Vasc Biol 20:1939–1945Google Scholar
  122. 122.
    Riddell DR, Vinogradov DV, Stannard AK, Chadwick N, Owen JS (1999) Identification and characterisation of LRP8 (apoER2) in human blood platelets. J Lipid Res 40:1925–1930Google Scholar
  123. 123.
    Riddell DR, Graham A, Owen JS (1997) Apolipoprotein E inhibits platelet aggregation through the L-arginine: nitric oxide pathway. Implications for vascular disease. J Biol Chem 272:89–95CrossRefGoogle Scholar
  124. 124.
    Stannard AK, Riddell DR, Sacre SM, Tagalakis AD, Langer C, Von Eckardstein A, Cullen P, Arthanasopoulos T, Dickson G, Owen JS (2001) Cell-derived apolipoprotein E (apoE) particles inhibit vascular cell adhesion molecule-1 (VCAM-1) expression in human endothelial cell. J Biol Chem 276:46011–46016CrossRefGoogle Scholar
  125. 125.
    Sacre SM, Stannard AK, Owen JS (2003) Apolipoprotein E isoforms differentially induce nitric oxide production in endothelial cells. FEBS Lett 540:181–187CrossRefGoogle Scholar
  126. 126.
    Avila EM, Holdsworth G, Sasaki N, Jackson RL, Harmony JA (1982) Apoprotein E suppresses phytohemagglutinin-activated phospholipid turnover in peripheral blood mononuclear cells. J Biol Chem 257:5900–5909Google Scholar
  127. 127.
    Hui DY, Harmony JAK (1980) Inhibition of calcium accumulation in mitogen-activated lymphocytes: role of membrane-bound plasma lipoproteins. Proc Natl Acad Sci USA 77:4764–4768Google Scholar
  128. 128.
    Kelly ME, Clay MA, Mistry MJ, Hsieh-Li HM, Harmony JA (1994) Apolipoprotein E inhibition of mitogen-activated T-lymphocytes: production of interleukin 2 with reduced biological activity. Cell Immunol 159:124–139CrossRefGoogle Scholar
  129. 129.
    Mistry MJ, Clay MA, Kelly ME, Steiner MA, Harmony JA (1995) Apolipoprotein E restricts interleukin-dependant T-lymphocyte proliferation at the G1A/G1B boundary. Cell Immunol 160:14–23CrossRefGoogle Scholar
  130. 130.
    Ishigami M, Swertfeger DK, Hui MS, Granholm NA, Hui DY (2000) Apolipoprotein E inhibition of vascular SMC proliferation but not the inhibition of migration is mediated through activation of inducible nitric oxide synthase. Arterioscler Thromb Vasc Biol 20:1020–1026Google Scholar
  131. 131.
    Swertfeger DK, Hui DY (2001) Apolipoprotein E receptor binding versus heparan sulfate proteoglycan binding in its regulation of smooth muscle cell migration and proliferation. J Biol Chem 276:25043–25048CrossRefGoogle Scholar
  132. 132.
    Kothapalli D, Fuki I, Ali K, Stewart SA, Zhao L, Yahil R, Kwiatkowski D, Hawthorne EA, FitzGerald GA, Phillips MC, Lund-Katz S, Puré E, Rader DJ, Assoian RK (2004) Antimitogenic effects of HDL and ApoE mediated by Cox-2 dependent IP activation. J Clin Invest 113:609–618CrossRefGoogle Scholar
  133. 133.
    Zhu Y, Hui DY (2003) Apolipoprotein E binding to low density lipoprotein receptor-related protein-1 inhibits cell migration via activation of cAMP-dependent protein kinase A. J Biol Chem 278:36257–36363CrossRefGoogle Scholar
  134. 134.
    Miyata M, Smith JD (1996) Apolipoprotein E allele-specific antioxidant activity and effects on cytotoxicity by oxidative insults and beta-amyloid peptides. Nat Genet 14:55–61CrossRefGoogle Scholar
  135. 135.
    Palinski W, Ord VA, Plump AS, Breslow JL, Steinberg D, Witztum JL (1994) ApoE-deficient mice are a model of lipoprotein oxidation in atherogenesis: demonstration of oxidation-specific epitopes in lesions and high titers of autoantibodies to malondialdehyde-lysine in serum. Arterioscler Thromb 14:605–616Google Scholar
  136. 136.
    Vogel T, Guo N, Guy R, Drezlich N, Krutzsch HC, Blake DA, Panet A, Roberts DD (1994) Apolipoprotein E: a potent inhibitor of endothelial and tumor cell proliferation. J Cell Biochem 54:299–308Google Scholar
  137. 137.
    Rees D, Sloane T, Jessup W, Dean RT, Kritharides L (1999) Apolipoprotein A-1 stimulates secretion of apolipoprotein E by foam cell macrophages. J Biol Chem 274:27952–27933CrossRefGoogle Scholar
  138. 138.
    Andreani-Mangeney M, Vandenbrouck Y, Janvier B, Girlich D, Bereziat G (1996) Transcriptional regulation of apolipoprotein E expression by cyclic AMP. FEBS Lett 397:155–158CrossRefGoogle Scholar
  139. 139.
    Von Eckardstein A, Langer C, Engel T (2001) ATP binding cassette transporter ABCA1 modulates the secretion of apoE from human monocyte-derived macrophages. FASEB J 15:1555–1561CrossRefGoogle Scholar
  140. 140.
    Garcia MA, Vazquez J, Gimenez C, Valdivieso F, Zafra F (1996) Transcription factor AP-2 regulate human apolipoprotein E/C-I/C-IV/C-II gene locus. J Biol Chem 271:7550–7556Google Scholar
  141. 141.
    Zuckerman S, O’Neal L (1994) Endotoxin and GM-CSF mediated down-regulation of macrophage apoE secretion is inhibited by a TNF-α specific monoclonal antibody. J Leukoc Biol 55:743–748Google Scholar
  142. 142.
    Zuckerman S, Evans G, O’Neal L (1992) Cytokine regulation of macrophage apoE secretion: opposing effects of GM-CSF and TGF-β. Atherosclerosis 96:203–221Google Scholar
  143. 143.
    Mazzone T, Gump H, Diller P, Getz GS (1987) Macrophage free cholesterol content regulates apolipoprotein E synthesis. J Biol Chem 262:11657–11662Google Scholar
  144. 144.
    Brand K, Mackman N, Curtiss L (1993) Interferon γ inhibits macrophage apolipoprotein E production by posttranslational mechanisms. J Clin Invest 91:2031–2039Google Scholar
  145. 145.
    Auwerx JH, Deeb S, Brunzell JD (1988) Transcriptional activation of the lipoprotein lipase and apolipoprotein E genes accompanies differentiation in some human macrophage-like cell lines. Biochemistry 27:2651–2655Google Scholar
  146. 146.
    Berg D, Calnek D, Grinnell B (1996) Trans-repressor BEF-1 phosphorylation. J Biol Chem 271:4589–4592CrossRefGoogle Scholar
  147. 147.
    Srivastava RA, Bhasin N, Srivastava N (1997) Apolipoprotein E gene expression in various tissues of mouse and regulation by estrogen. Biochem Mol Biol Int 38:91–101Google Scholar
  148. 148.
    Ogbonna G, Theriault A, Adeli K (1993) Hormonal regulation of human apolipoprotein E gene expression in HepG2 cells. Int J Biochem 25:635–640Google Scholar
  149. 149.
    Lucas M, Iverius PH, Strickland DK, Mazzone T (1997) Lipoprotein lipase reduces secretion of apolipoprotein E from macrophages. J Biol Chem 272:13000–13005CrossRefGoogle Scholar
  150. 150.
    Zuckerman SH, Evans GF, O’Neal L (1993) Exogenous glucocorticoids increase macrophage secretion of apoE by cholesterol-independent pathways. Atherosclerosis 103:43–54Google Scholar
  151. 151.
    Castilho LN, Chamberland A, Boulet L, Davignon J, Cohn JS, Bernier L (2003) Effect of atorvastatin on apoE and apoC-I synthesis and secretion by THP-1 macrophages. J Cardiovasc Pharmacol 42:251–257CrossRefGoogle Scholar
  152. 152.
    Huang ZH, Gu D, Mazzone T (2004) Oleic acid modulates the post-translational glycosylation of macrophage ApoE to increase its secretion. J Biol Chem 279:29195–29201CrossRefGoogle Scholar
  153. 153.
    Laffitte BA, Repa JJ, Joseph SB, Wilpitz DC, Kast HR, Mangelsdorf DJ, Tontonoz P (2001) LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adipocytes. Proc Natl Acad Sci USA 98:507–512CrossRefGoogle Scholar
  154. 154.
    Cader A, Steinberg F, Mazzone T, Chait A (1997) Mechanisms of enhanced macrophage apoE secretion by oxidised LDL. J Lipid Res 38:981–991Google Scholar
  155. 155.
    Galetto R, Albajar M, Polanco JI, Zakin MM, Rodriguez-Rey JC (2001) Identification of a peroxisome-proliferator-activated-receptor response element in the apolipoprotein E gene control region. Biochem J 357:521–527CrossRefPubMedGoogle Scholar
  156. 156.
    Vandenbrouck Y, Janvier B, Loriette C, Bereziat G, Mangeney-Andreani M (1994) The modulation of apolipoprotein E expression by 3:3’-5-triiodothyronine in HepG2 cells occurs at transcriptional and post-transcriptional levels. Eur J Biochem 224:463–471Google Scholar
  157. 157.
    Duan H, Li Z, Mazzone T (1995) Tumor necrosis factor-α modulates monocyte/macrophage apoprotein E gene expression. J Clin Invest 96:915–922Google Scholar
  158. 158.
    Basheeruddin K, Rechtoris C, Mazzone T (1994) Evaluation of the role of Ap-1 like proteins in the enhanced apolipoprotein E gene transcription accompanying phorbol ester induced macrophage differentiation. Biochim Biophys Acta 1218:235–241Google Scholar
  159. 159.
    Larkin L, Khachigian LM, Jessup W (2000) Regulation of apolipoprotein E production in macrophages. Int J Mol Med 6:253–258Google Scholar
  160. 160.
    Artiga MJ, Bullido MJ, Sastre I, Recuero M, Garcia MA, Aldudo J, Vazquez J, Valdivieso F (1998) Allelic polymorphisms in the transcriptional regulatory region of apolipoprotein E gene. FEBS Lett 421:105–108CrossRefPubMedGoogle Scholar
  161. 161.
    Mui S, Briggs M, Chung H, Wallace RB, Gomez-Isla T, Rebeck GW, Hyman BT (1996) A newly identified polymorphism in the apolipoprotein E enhancer region is associated with Alzheimer’s disease and strongly with the epsilon 4 allele. Neurology 47:196–201Google Scholar
  162. 162.
    Artiga MJ, Bullido MJ, Frank A, Sastre I, Recuero M, Garcia MA, Lendon CL, Han SW, Morris JC, Vazquez J, Goate A, Valdivieso F (1998) Risk for Alzheimer’s disease correlates with transcriptional activity of the APOE gene. Hum Mol Genet 7:1887–1892CrossRefPubMedGoogle Scholar
  163. 163.
    Laws SM, Hone E, Gandy S, Martins RN (2003) Expanding the association between the APOE gene and the risk of Alzheimer’s disease: possible roles for APOE promoter polymorphisms and alterations in APOE transcription. J Neurochem 84:1215–1236CrossRefGoogle Scholar
  164. 164.
    Lambert JC, Brousseau T, Defosse V, Evans A, Arveiler D, Ruidavets JB, Haas B, Cambou JP, Luc G, Ducimetiere P, Cambien F, Chartier-Harlin MC, Amouyel P (2000) Independent association of an APOE gene promoter polymorphism with increased risk of myocardial infarction and decreased APOE plasma concentration-the ECTIM study. Hum Mol Genet 9:57–61CrossRefGoogle Scholar
  165. 165.
    Vitanen L, Pihlajamaki J, Miettinen R, Karkkainen P, Vauhkonen I, Halonen P, Kareinen A, Lehto S, Laakso M (2001) Apolipoprotein E gene promoter (-219G/T) polymorphism is associated with premature coronary heart disease. J Mol Med 79:732–737Google Scholar
  166. 166.
    Moreno JA, Lopez-Miranda J, Marin C, Gomez P, Perez-Martinez P, Fuentes F, Fernandez de la Puebla RA, Paniagua JA, Ordovas JM, Perez-Jimenez F (2003) The influence of the apolipoprotein E gene promoter (-219G/T) polymorphism on postprandial lipoprotein metabolism in young normolipemic males. J Lipid Res 44:2059–2064CrossRefGoogle Scholar
  167. 167.
    Garcia-Otin AL, Civeira F, Aristegui R, Diaz C, Recalde D, Sol JM, Masramon X, Hernandez G, Pocovi M, ATOMIX Study Group (2002) Atorvastatin in mixed dyslipidemia. Eur J Clin Invest 32:421–428Google Scholar
  168. 168.
    Alla CM, Taylor S, Taylor JM (1997) Two hepatic enhancers HCR.1 and HCR.2, coordinate the liver expression of the entire human apolipoprotein E/C-I/C-IV/C-II gene cluster. J Biol Chem 272:29113–29119CrossRefGoogle Scholar
  169. 169.
    Grehan S, Rse E, Taylor JM (2001) Two distal downstream enhancers direct expression of the human apolipoprotein E gene in astrocytes in the brain. J Neurosci 21:812–822Google Scholar
  170. 170.
    Grehan S, Allan C, Tse E, Walker D, Taylor JM (2001) Expression of the apolipoprotein E gene in the skin is controlled by a unique downstream enhancer. J Invest Dermatol 116:77–84CrossRefGoogle Scholar
  171. 171.
    Shih S-J, Allan C, Grehan S, Tse E, Moran C, Taylor JM (2000) Duplicated downstream enhancers control expression of the human apolipoprotein E gene in macrophages and adipose tissue. J Biol Chem 275:31567–31572CrossRefGoogle Scholar
  172. 172.
    Basheerudin K, Rechtoris C, Mazzone T (1992) Transcriptional and post-transcriptional control of apolipoprotein E expression in differentiating human monocytes. J Biol Chem 267:1219–1224Google Scholar
  173. 173.
    Deng J, Rudick V, Dory L (1995) Lysosomal degradation and sorting of apolipoprotein E in macrophages. J Lipid Res 36:2129–2140Google Scholar
  174. 174.
    Wenner C, Lorkowski S, Engel T, Cullen P (2001) Apolipoprotein E in macrophages and hepatocytes is degraded via the proteasomal pathway. Biochem Biophys Res Commun 282:608–614CrossRefGoogle Scholar
  175. 175.
    Bortnick AE, Rothblat GH, Stoudt G, Hoppe KL, Royer LJ, McNeish J, Francone OL (2000) The correlation of ATP-binding cassette transporter 1 mRNA levels with cholesterol efflux from various cell lines. J Biol Chem 275:28634–28640CrossRefGoogle Scholar
  176. 176.
    Mensenkamp AR, Jong MC, can Goor H, van Luyn MJ, Bloks V, Havinga R, Voshol PJ, Hofker MH, van Dijk KW, Havekes LM, Kuipers F (1999) Apolipoprotein E participates in the regulation of low density lipoprotein-triglyceride secretion by the liver. J Biol Chem 274:35711–35788CrossRefGoogle Scholar
  177. 177.
    Fazio S, Linton MF, Swift LL (2000) The cell biology and physiologic relevance of apoE recycling. Trends Cardiovasc Med 10:23–30Google Scholar
  178. 178.
    Fazio S, Linton MF, Hasty AH, Swift LL (1999) Recycling of apolipoprotein E in mouse liver. J Biol Chem 274:8247–8253CrossRefGoogle Scholar
  179. 179.
    Swift LL, Farkas MH, Major AS, Valyi-Nagy K, Linton MF, Fazio S (2001) A recycling pathway for resecretion of internalized apolipoprotein E in liver cells. J Biol Chem 276:22965–22970CrossRefGoogle Scholar
  180. 180.
    Farkas MH, Weisgraber KH, Shepherd VL, Linton MF, Fazio S, Swift LL (2004) The recycling of apolipoprotein E and its amino-terminal 22 kDa fragment: evidence for multiple redundant pathways. J Lipid Res 45:1546–1554CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Kirsty Greenow
    • 1
  • Nigel J. Pearce
    • 2
  • Dipak P. Ramji
    • 1
    Email author
  1. 1.Cardiff School of BiosciencesCardiff UniversityCardiffUK
  2. 2.GlaxoSmithKlineGunnels Wood RoadStevenageUK

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