Journal of Molecular Medicine

, Volume 96, Issue 5, pp 361–371 | Cite as

Cell-specific production, secretion, and function of apolipoprotein E

  • Maaike Kockx
  • Mathew Traini
  • Leonard Kritharides


Apolipoprotein E (apoE) is a 34-kDa glycoprotein that is secreted from many cells throughout the body. ApoE is best known for its role in lipoprotein metabolism. Recent studies underline the association of circulating lipoprotein-associated apoE levels and the development for cardiovascular disease (CVD). Besides its well-established role in pathology of CVD, it is also implicated in neurodegenerative diseases and recent new data on adipose-produced apoE point to a novel metabolic role for apoE in obesity. The regulation of apoE production and secretion is remarkably cell and tissue specific. Here, we summarize recent insights into the differential regulation apoE production and secretion by hepatocytes, monocytes/macrophages, adipocytes, and the central nervous system and relevant variations in apoE biochemistry and function.


Apolipoprotein E Constitutive secretion Macrophages Adipocytes Astrocytes Neuronal cells 



This work has been funded by NHMRC Program Grant 482820.


  1. 1.
    van Dijk KW, Hofker MH, Havekes LM (1999) Dissection of the complex role of apolipoprotein E in lipoprotein metabolism and atherosclerosis using mouse models. Curr Atheroscler Rep 1:101–107CrossRefPubMedGoogle Scholar
  2. 2.
    Pechlaner R, Tsimikas S, Yin X, Willeit P, Baig F, Santer P, Oberhollenzer F, Egger G, Witztum JL, Alexander VJ et al. (2017) Very-low-density lipoprotein-associated apolipoproteins predict cardiovascular events and are lowered by inhibition of APOC-III. J Am Coll Cardiol 69:789–800Google Scholar
  3. 3.
    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 96:2170–2179CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Ali K, Middleton M, Puré E, Rader DJ (2005) Apolipoprotein E suppresses the type I inflammatory response in vivo. Circ Res 97:922–927CrossRefPubMedGoogle Scholar
  5. 5.
    van den Elzen P, Garg S, León L et al (2005) Apolipoprotein-mediated pathways of lipid antigen presentation. Nature 437:906–910CrossRefPubMedGoogle Scholar
  6. 6.
    Kothapalli D, Fuki I, Ali K, Stewart SA, Zhao L, Yahil R, Kwiatkowski D, Hawthorne EA, FitzGerald GA, Phillips MC et al. (2004) Antimitogenic effects of HDL and APOE mediated by Cox-2-dependent IP activation. J Clin Invest 113:609–618Google Scholar
  7. 7.
    Li Y-H, Liu L (2014) Apolipoprotein E synthesized by adipocyte and apolipoprotein E carried on lipoproteins modulate adipocyte triglyceride content. Lipids Health Dis 13:136CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Huang ZH, Reardon CA, Getz GS, Maeda N, Mazzone T (2015) Selective suppression of adipose tissue apoE expression impacts systemic metabolic phenotype and adipose tissue inflammation. J Lipid Res 56:215–226CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Arbones-Mainar JM, Johnson LA, Altenburg MK, Maeda N (2008) Differential modulation of diet-induced obesity and adipocyte functionality by human apolipoprotein E3 and E4 in mice. Int J Obes 32:1595–1605CrossRefGoogle Scholar
  10. 10.
    Xu Q, Bernardo A, Walker D, Kanegawa T, Mahley RW, Huang Y (2006) Profile and regulation of apolipoprotein E (ApoE) expression in the CNS in mice with targeting of green fluorescent protein gene to the ApoE locus. J Neurosci 26:4985–4994CrossRefPubMedGoogle Scholar
  11. 11.
    Gafencu AV, Robciuc MR, Fuior E, Zannis VI, Kardassis D, Simionescu M (2007) Inflammatory signaling pathways regulating ApoE gene expression in macrophages. J Biol Chem 282:21776–21785CrossRefPubMedGoogle Scholar
  12. 12.
    Chang DJ, Paik YK, Leren TP, Walker DW, Howlett GJ, Taylor JM (1990) Characterization of a human apolipoprotein E gene enhancer element and its associated protein factors. J Biol Chem 265:9496–9504PubMedGoogle Scholar
  13. 13.
    Berg DT, Calnek DS, Grinnell BW (1995) The human apolipoprotein E gene is negatively regulated in human liver HepG2 cells by the transcription factor BEF-1. J Biol Chem 270:15447–15450CrossRefPubMedGoogle Scholar
  14. 14.
    García MA, Vázquez J, Giménez C, Valdivieso F, Zafra F (1996) Transcription factor AP-2 regulates human apolipoprotein E gene expression in astrocytoma cells. J Neurosci 16:7550–7556CrossRefPubMedGoogle Scholar
  15. 15.
    Salero E, Pérez-Sen R, Aruga J, Giménez C, Zafra F (2001) Transcription factors Zic1 and Zic2 bind and transactivate the apolipoprotein E gene promoter. J Biol Chem 276:1881–1888CrossRefPubMedGoogle Scholar
  16. 16.
    Salero E, Giménez C, Zafra F (2003) Identification of a non-canonical E-box motif as a regulatory element in the proximal promoter region of the apolipoprotein E gene. Biochem J 370:979–986CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Stavri S, Simionescu M, Kardassis D, Gafencu AV (2015) Krüppel-like factor 4 synergizes with CREB to increase the activity of apolipoprotein E gene promoter in macrophages. Biochem Biophys Res Commun 468:66–72CrossRefPubMedGoogle Scholar
  18. 18.
    Simonet WS, Bucay N, Lauer SJ, Taylor JM (1993) A far-downstream hepatocyte-specific control region directs expression of the linked human apolipoprotein E and C-I genes in transgenic mice. J Biol Chem 268:8221–8229PubMedGoogle Scholar
  19. 19.
    Paik YK, Chang DJ, Reardon CA, Walker MD, Taxman E, Taylor JM (1988) Identification and characterization of transcriptional regulatory regions associated with expression of the human apolipoprotein E gene. J Biol Chem 263:13340–13349PubMedGoogle Scholar
  20. 20.
    Allan CM, Walker D, Taylor JM (1995) Evolutionary duplication of a hepatic control region in the human apolipoprotein E gene locus. Identification of a second region that confers high level and liver-specific expression of the human apolipoprotein E gene in transgenic mice. J Biol Chem 270:26278–26281CrossRefPubMedGoogle Scholar
  21. 21.
    Shih SJ, 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 275:31567–31572CrossRefPubMedGoogle Scholar
  22. 22.
    Grehan S, Tse E, Taylor JM (2001) Two distal downstream enhancers direct expression of the human apolipoprotein E gene to astrocytes in the brain. J Neurosci 21:812–822CrossRefPubMedGoogle Scholar
  23. 23.
    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 U S A 98:507–512CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Liang Y, Lin S, Beyer TP, Zhang Y, Wu X, Bales KR, DeMattos RB, May PC, Li SD, Jiang XC et al. (2004) A liver X receptor and retinoid X receptor heterodimer mediates apolipoprotein E expression, secretion and cholesterol homeostasis in astrocytes. J Neurochem 88:623–634Google Scholar
  25. 25.
    Ramos MC, Matías S, Artiga MJ et al (2005) Neuronal specific regulatory elements in apolipoprotein E gene proximal promoter. Neuroreport 16:1027–1030CrossRefPubMedGoogle Scholar
  26. 26.
    Trusca VG, Fuior EV, Fenyo IM, Kardassis D, Simionescu M, Gafencu AV (2017) Differential action of glucocorticoids on apolipoprotein E gene expression in macrophages and hepatocytes. PLoS One 12:e0174078CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Xu Q, Walker D, Bernardo A, Brodbeck J, Balestra ME, Huang Y (2008) Intron-3 retention/splicing controls neuronal expression of apolipoprotein E in the CNS. J Neurosci 28:1452–1459CrossRefPubMedGoogle Scholar
  28. 28.
    Ma Y, Smith CE, Lai C-Q, Irvin MR, Parnell LD, Lee YC, Pham L, Aslibekyan S, Claas SA, Tsai MY et al. (2015) Genetic variants modify the effect of age on APOE methylation in the Genetics of Lipid Lowering Drugs and Diet Network study. Aging Cell 14:49–59Google Scholar
  29. 29.
    Seitz A, Gourevitch D, Zhang X-M, Clark L, Chen P, Kragol M, Levenkova N, Rux J, Samulewicz S, Heber-Katz E (2005) Sense and antisense transcripts of the apolipoprotein E gene in normal and ApoE knockout mice, their expression after spinal cord injury and corresponding human transcripts. Hum Mol Genet 14:2661–2670CrossRefPubMedGoogle Scholar
  30. 30.
    Pencheva N, Tran H, Buss C, Huh D, Drobnjak M, Busam K, Tavazoie SF (2012) Convergent multi-miRNA targeting of ApoE drives LRP1/LRP8-dependent melanoma metastasis and angiogenesis. Cell 151:1068–1082CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Kockx M, Guo DL, Huby T, Lesnik P, Kay J, Sabaretnam T, Jary E, Hill M, Gaus K, Chapman J et al. (2007) Secretion of apolipoprotein E from macrophages occurs via a protein kinase A and calcium-dependent pathway along the microtubule network. Circ Res 101:607–616Google Scholar
  32. 32.
    Burgess JW, Gould DR, Marcel YL (1998) The HepG2 extracellular matrix contains separate heparinase- and lipid-releasable pools of ApoE. Implications for hepatic lipoprotein metabolism. J Biol Chem 273:5645–5654CrossRefPubMedGoogle Scholar
  33. 33.
    Zhao Y, Mazzone T (2000) Transport and processing of endogenously synthesized ApoE on the macrophage cell surface. J Biol Chem 275:4759–4765CrossRefPubMedGoogle Scholar
  34. 34.
    Dory L (1991) Regulation of apolipoprotein E secretion by high density lipoprotein 3 in mouse macrophages. J Lipid Res 32:783–792PubMedGoogle Scholar
  35. 35.
    Kockx M, Rye K-A, Gaus K, Quinn CM, Wright J, Sloane T, Sviridov D, Fu Y, Sullivan D, Burnett JR et al. (2004) Apolipoprotein A-I-stimulated apolipoprotein E secretion from human macrophages is independent of cholesterol efflux. J Biol Chem 279:25966–25977Google Scholar
  36. 36.
    Karunakaran D, Kockx M, Owen DM, Burnett JR, Jessup W, Kritharides L (2013) Protein kinase C controls vesicular transport and secretion of apolipoprotein E from primary human macrophages. J Biol Chem 288:5186–5197CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Kockx M, Guo DL, Traini M, Gaus K, Kay J, Wimmer-Kleikamp S, Rentero C, Burnett JR, le Goff W, van Eck M et al. (2009) Cyclosporin A decreases apolipoprotein E secretion from human macrophages via a protein phosphatase 2B-dependent and ATP-binding cassette transporter A1 (ABCA1)-independent pathway. J Biol Chem 284:24144–24154Google Scholar
  38. 38.
    Kockx M, Karunakaran D, Traini M, Xue J, Huang KY, Nawara D, Gaus K, Jessup W, Robinson PJ, Kritharides L (2014) Pharmacological inhibition of dynamin II reduces constitutive protein secretion from primary human macrophages. PLoS One 9:e111186CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Liu J, Farmer JD, Lane WS et al (1991) Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell 66:807–815CrossRefPubMedGoogle Scholar
  40. 40.
    Braesch-Andersen S, Paulie S, Smedman C, Mia S, Kumagai-Braesch M (2013) ApoE production in human monocytes and its regulation by inflammatory cytokines. PLoS One 8:e79908CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Dekroon RM, Armati PJ (2002) The effects of oxidative stress and altered intracellular calcium levels on vesicular transport of apoE-EGFP. Cell Biol Int 26:407–420CrossRefPubMedGoogle Scholar
  42. 42.
    Kimura A, Hata S, Suzuki T (2015) Stabilization of intracellular trafficking and metabolism of amyloid β-protein precursor and Alcadein β by apolipoprotein E. FEBS Lett 589:2394–2400CrossRefPubMedGoogle Scholar
  43. 43.
    Finan GM, Realubit R, Chung S, Lütjohann D, Wang N, Cirrito JR, Karan C, Kim TW (2016) Bioactive compound screen for pharmacological enhancers of apolipoprotein E in primary human astrocytes. Cell Chem Biol 23:1526–1538CrossRefPubMedGoogle Scholar
  44. 44.
    Ito J-I, Nagayasu Y, Miura Y, Yokoyama S, Michikawa M (2014) Astrocyte′s endogenous apoE generates HDL-like lipoproteins using previously synthesized cholesterol through interaction with ABCA1. Brain Res 1570:1–12CrossRefPubMedGoogle Scholar
  45. 45.
    Yue L, Mazzone T (2011) Endogenous adipocyte apolipoprotein E is colocalized with caveolin at the adipocyte plasma membrane. J Lipid Res 52:489–498CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Zannis VI, Breslow JL, SanGiacomo TR et al (1981) Characterization of the major apolipoproteins secreted by two human hepatoma cell lines. Biochemistry 20:7089–7096CrossRefPubMedGoogle Scholar
  47. 47.
    Ghiselli G, Beigel Y, Soma M, Gotto AM (1986) Plasma catabolism of human apolipoprotein E isoproteins: lack of conversion of the doubly sialylated form to the asialo form in plasma. Metab Clin Exp 35:399–403CrossRefPubMedGoogle Scholar
  48. 48.
    Pitas RE, Boyles JK, Lee SH, Foss D, Mahley RW (1987) Astrocytes synthesize apolipoprotein E and metabolize apolipoprotein E-containing lipoproteins. Biochim Biophys Acta 917:148–161CrossRefPubMedGoogle Scholar
  49. 49.
    Yamauchi K, Tozuka M, Hidaka H, Hidaka E, Kondo Y, Katsuyama T (1999) Characterization of apolipoprotein E-containing lipoproteins in cerebrospinal fluid: effect of phenotype on the distribution of apolipoprotein E. Clin Chem 45:1431–1438PubMedGoogle Scholar
  50. 50.
    Hussain MM, Bucher NL, Faris B, Franzblau C, Zannis VI (1988) Tissue-specific posttranslational modification of rat apoE. Synthesis of sialated apoE forms by neonatal rat aortic smooth muscle cells. J Lipid Res 29:915–923PubMedGoogle Scholar
  51. 51.
    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 264:9094–9101PubMedGoogle Scholar
  52. 52.
    Lee Y, Kockx M, Raftery MJ, Jessup W, Griffith R, Kritharides L (2010) Glycosylation and sialylation of macrophage-derived human apolipoprotein E analyzed by SDS-PAGE and mass spectrometry: evidence for a novel site of glycosylation on Ser290. Mol Cell Proteomics 9:1968–1981CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Halim A, Rüetschi U, Larson G, Nilsson J (2013) LC-MS/MS characterization of O-glycosylation sites and glycan structures of human cerebrospinal fluid glycoproteins. J Proteome Res 12:573–584CrossRefPubMedGoogle Scholar
  54. 54.
    Nilsson J, Rüetschi U, Halim A, Hesse C, Carlsohn E, Brinkmalm G, Larson G (2009) Enrichment of glycopeptides for glycan structure and attachment site identification. Nat Methods 6:809–811CrossRefPubMedGoogle Scholar
  55. 55.
    Zielinska DF, Gnad F, Wiśniewski JR, Mann M (2010) Precision mapping of an in vivo N-glycoproteome reveals rigid topological and sequence constraints. Cell 141:897–907CrossRefPubMedGoogle Scholar
  56. 56.
    Medzihradszky KF, Kaasik K, Chalkley RJ (2015) Tissue-specific glycosylation at the glycopeptide level. Mol Cell Proteomics 14:2103–2110CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Huang ZH, Gu D, Mazzone T (2004) Oleic acid modulates the post-translational glycosylation of macrophage ApoE to increase its secretion. J Biol Chem 279:29195–29201CrossRefPubMedGoogle Scholar
  58. 58.
    Marmillot P, Rao MN, Liu QH, Lakshman MR (1999) Desialylation of human apolipoprotein E decreases its binding to human high-density lipoprotein and its ability to deliver esterified cholesterol to the liver. Metab Clin Exp 48:1184–1192CrossRefPubMedGoogle Scholar
  59. 59.
    Aleshkov SB, Li X, Lavrentiadou SN, Zannis VI (1999) Contribution of cysteine 158, the glycosylation site threonine 194, the amino- and carboxy-terminal domains of apolipoprotein E in the binding to amyloid peptide beta (1-40). Biochemistry 38:8918–8925CrossRefPubMedGoogle Scholar
  60. 60.
    Chua C-C, Lim M-L, Wong B-S (2010) Altered apolipoprotein E glycosylation is associated with Abeta(42) accumulation in an animal model of Niemann-Pick Type C disease. J Neurochem 112:1619–1626CrossRefPubMedGoogle Scholar
  61. 61.
    Basu SK, Brown MS, Ho YK, Havel RJ, Goldstein JL (1981) Mouse macrophages synthesize and secrete a protein resembling apolipoprotein E. Proc Natl Acad Sci U S A 78:7545–7549CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Werb Z, Chin JR (1983) Onset of apoprotein E secretion during differentiation of mouse bone marrow-derived mononuclear phagocytes. J Cell Biol 97:1113–1118CrossRefPubMedGoogle Scholar
  63. 63.
    Tedla N, Glaros EN, Brunk UT, Jessup W, Garner B (2004) Heterogeneous expression of apolipoprotein-E by human macrophages. Immunology 113:338–347CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Takemura R, Werb Z (1984) Secretory products of macrophages and their physiological functions. Am J Phys 246:C1–C9CrossRefGoogle Scholar
  65. 65.
    Leitinger N, Schulman IG (2013) Phenotypic polarization of macrophages in atherosclerosis. Arterioscler Thromb Vasc Biol 33:1120–1126CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Li K, Ching D, Luk FS, Raffai RL (2015) Apolipoprotein E enhances microRNA-146a in monocytes and macrophages to suppress nuclear factor-κB-driven inflammation and atherosclerosis. Circ Res 117:e1–e11CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Bouchareychas L, Pirault J, Saint-Charles F, Deswaerte V, le Roy T, Jessup W, Giral P, le Goff W, Huby T, Gautier EL, Lesnik P (2015) Promoting macrophage survival delays progression of pre-existing atherosclerotic lesions through macrophage-derived apoE. Cardiovasc Res 108:111–123CrossRefPubMedGoogle Scholar
  68. 68.
    Huang Y, Liu XQ, Rall SC et al (1998) Overexpression and accumulation of apolipoprotein E as a cause of hypertriglyceridemia. J Biol Chem 273:26388–26393CrossRefPubMedGoogle Scholar
  69. 69.
    Zhang SH, Reddick RL, Piedrahita JA, Maeda N (1992) Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science 258:468–471CrossRefPubMedGoogle Scholar
  70. 70.
    Murphy AJ, Akhtari M, Tolani S, Pagler T, Bijl N, Kuo CL, Wang M, Sanson M, Abramowicz S, Welch C et al. (2011) ApoE regulates hematopoietic stem cell proliferation, monocytosis, and monocyte accumulation in atherosclerotic lesions in mice. J Clin Invest 121:4138–4149Google Scholar
  71. 71.
    Khallou-Laschet J, Varthaman A, Fornasa G, Compain C, Gaston AT, Clement M, Dussiot M, Levillain O, Graff-Dubois S, Nicoletti A, Caligiuri G (2010) Macrophage plasticity in experimental atherosclerosis. PLoS One 5:e8852Google Scholar
  72. 72.
    Baitsch D, Bock HH, Engel T, Telgmann R, Muller-Tidow C, Varga G, Bot M, Herz J, Robenek H, von Eckardstein A, Nofer JR (2011) Apolipoprotein E induces antiinflammatory phenotype in macrophages. Arterioscler Thromb Vasc Biol 31:1160–1168CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Huang ZH, Reardon CA, Subbaiah PV, Getz GS, Mazzone T (2013) ApoE derived from adipose tissue does not suppress atherosclerosis or correct hyperlipidemia in apoE knockout mice. J Lipid Res 54:202–213CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Huang ZH, Reardon CA, Mazzone T (2006) Endogenous ApoE expression modulates adipocyte triglyceride content and turnover. Diabetes 55:3394–3402CrossRefPubMedGoogle Scholar
  75. 75.
    Huang ZH, Gu D, Mazzone T (2009) Role of adipocyte-derived apoE in modulating adipocyte size, lipid metabolism, and gene expression in vivo. Am J Physiol Endocrinol Metab 296:E1110–E1119CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Lasrich D, Bartelt A, Grewal T, Heeren J (2015) Apolipoprotein E promotes lipid accumulation and differentiation in human adipocytes. Exp Cell Res 337:94–102CrossRefPubMedGoogle Scholar
  77. 77.
    Hofmann SM, Perez-Tilve D, Greer TM, Coburn BA, Grant E, Basford JE, Tschop MH, Hui DY (2008) Defective lipid delivery modulates glucose tolerance and metabolic response to diet in apolipoprotein E-deficient mice. Diabetes 57:5–12CrossRefPubMedGoogle Scholar
  78. 78.
    Elosua R, Demissie S, Cupples LA, Meigs JB, Wilson PWF, Schaefer EJ, Corella D, Ordovas JM (2003) Obesity modulates the association among APOE genotype, insulin, and glucose in men. Obes Res 11:1502–1508CrossRefPubMedGoogle Scholar
  79. 79.
    Mahley RW (2016) Apolipoprotein E: from cardiovascular disease to neurodegenerative disorders. J Mol Med 94:739–746CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Nordestgaard LT, Tybjærg-Hansen A, Nordestgaard BG, Frikke-Schmidt R (2015) Loss-of-function mutation in ABCA1 and risk of Alzheimer’s disease and cerebrovascular disease. Alzheimers Dement 11:1430–1438CrossRefPubMedGoogle Scholar
  81. 81.
    Gaudreault N, Kumar N, Posada JM, Stephens KB, Reyes de Mochel NS, Eberle D, Olivas VR, Kim RY, Harms MJ, Johnson S et al. (2012) ApoE suppresses atherosclerosis by reducing lipid accumulation in circulating monocytes and the expression of inflammatory molecules on monocytes and vascular endothelium. Arterioscler Thromb Vasc Biol 32:264–272Google Scholar
  82. 82.
    van der Valk FM, Kuijk C, Verweij SL, Stiekema LCA, Kaiser Y, Zeerleder S, Nahrendorf M, Voermans C, Stroes ESG (2017) Increased haematopoietic activity in patients with atherosclerosis. Eur Heart J 38:425–432PubMedGoogle Scholar
  83. 83.
    Zechner R, Moser R, Newman TC, Fried SK, Breslow JL (1991) Apolipoprotein E gene expression in mouse 3T3-L1 adipocytes and human adipose tissue and its regulation by differentiation and lipid content. J Biol Chem 266:10583–10588PubMedGoogle Scholar
  84. 84.
    Huang ZH, Espiritu DJ, Uy A, Holterman AX, Vitello J, Mazzone T (2011) Adipose tissue depot-specific differences in adipocyte apolipoprotein E expression. Metab Clin Exp 60:1692–1701CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Atkinson RD, Coenen KR, Plummer MR, Gruen ML, Hasty AH (2008) Macrophage-derived apolipoprotein E ameliorates dyslipidemia and atherosclerosis in obese apolipoprotein E-deficient mice. Am J Physiol Endocrinol Metab 294:E284–E290CrossRefPubMedGoogle Scholar
  86. 86.
    Giau VV, Bagyinszky E, An SSA, Kim SY (2015) Role of apolipoprotein E in neurodegenerative diseases. Neuropsychiatr Dis Treat 11:1723–1737CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Chang T-Y, Chang C (2017) ApoE and lipid homeostasis in Alzheimer’s disease: introduction to the thematic review series. J Lipid Res 58:823CrossRefPubMedGoogle Scholar
  88. 88.
    Boyles JK, Pitas RE, Wilson E, Mahley RW, Taylor JM (1985) Apolipoprotein E associated with astrocytic glia of the central nervous system and with nonmyelinating glia of the peripheral nervous system. J Clin Invest 76:1501–1513CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Dekroon RM, Armati PJ (2001) Synthesis and processing of apolipoprotein E in human brain cultures. Glia 33:298–305CrossRefPubMedGoogle Scholar
  90. 90.
    Keren-Shaul H, Spinrad A, Weiner A et al (2017) A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169:1276–1290.e17CrossRefPubMedGoogle Scholar
  91. 91.
    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 U S A 82:203–207CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Van Dooren T, Muyllaert D, Borghgraef P et al (2006) Neuronal or glial expression of human apolipoprotein e4 affects parenchymal and vascular amyloid pathology differentially in different brain regions of double- and triple-transgenic mice. Am J Pathol 168:245–260CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Buttini M, Masliah E, Yu G-Q, Palop JJ, Chang S, Bernardo A, Lin C, Wyss-Coray T, Huang Y, Mucke L (2010) Cellular source of apolipoprotein E4 determines neuronal susceptibility to excitotoxic injury in transgenic mice. Am J Pathol 177:563–569CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Bekris LM, Galloway NM, Montine TJ, Schellenberg GD, Yu CE (2010) APOE mRNA and protein expression in postmortem brain are modulated by an extended haplotype structure. Am J Med Genet B Neuropsychiatr Genet 153B:409–417CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Dean B, Laws SM, Hone E, Taddei K, Scarr E, Thomas EA, Harper C, McClean C, Masters C, Lautenschlager N et al. (2003) Increased levels of apolipoprotein E in the frontal cortex of subjects with schizophrenia. Biol Psychiatry 54:616–622Google Scholar
  96. 96.
    Yu C-E, Foraker J (2015) Epigenetic considerations of the APOE gene. [corrected]. Biomol Concepts 6:77–84PubMedGoogle Scholar
  97. 97.
    Becker L, Gharib SA, Irwin AD, Wijsman E, Vaisar T, Oram JF, Heinecke JW (2010) A macrophage sterol-responsive network linked to atherogenesis. Cell Metab 11:125–135CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Kockx M, Dinnes DL, Huang K-Y, Sharpe LJ, Jessup W, Brown AJ, Kritharides L (2012) Cholesterol accumulation inhibits ER to Golgi transport and protein secretion: studies of apolipoprotein E and VSVGt. Biochem J 447:51–60CrossRefPubMedGoogle Scholar
  99. 99.
    Liscum L, Underwood KW (1995) Intracellular cholesterol transport and compartmentation. J Biol Chem 270:15443–15446CrossRefPubMedGoogle Scholar
  100. 100.
    Fan J, Stukas S, Wong C, Chan J, May S, DeValle N, Hirsch-Reinshagen V, Wilkinson A, Oda MN, Wellington CL (2011) An ABCA1-independent pathway for recycling a poorly lipidated 8.1 nm apolipoprotein E particle from glia. J Lipid Res 52:1605–1616CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Jiang Q, Lee CYD, Mandrekar S, Wilkinson B, Cramer P, Zelcer N, Mann K, Lamb B, Willson TM, Collins JL et al. (2008) ApoE promotes the proteolytic degradation of Abeta. Neuron 58:681–693Google Scholar
  102. 102.
    Kim WS, Rahmanto AS, Kamili A, Rye KA, Guillemin GJ, Gelissen IC, Jessup W, Hill AF, Garner B (2007) Role of ABCG1 and ABCA1 in regulation of neuronal cholesterol efflux to apolipoprotein E discs and suppression of amyloid-beta peptide generation. J Biol Chem 282:2851–2861CrossRefPubMedGoogle Scholar
  103. 103.
    Burgess BL, Parkinson PF, Racke MM, Hirsch-Reinshagen V, Fan J, Wong C, Stukas S, Theroux L, Chan JY, Donkin J et al. (2008) ABCG1 influences the brain cholesterol biosynthetic pathway but does not affect amyloid precursor protein or apolipoprotein E metabolism in vivo. J Lipid Res 49:1254–1267Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Maaike Kockx
    • 1
    • 2
  • Mathew Traini
    • 1
    • 2
  • Leonard Kritharides
    • 1
    • 2
    • 3
  1. 1.Concord Repatriation General HospitalANZAC Research InstituteSydneyAustralia
  2. 2.Sydney Medical SchoolUniversity of SydneySydneyAustralia
  3. 3.Department of CardiologyConcord Repatriation General HospitalConcordAustralia

Personalised recommendations