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Apolipoprotein E isoforms and lipoprotein metabolism
Abstract
Apolipoprotein (apo) E is a 299‐residue protein which functions as a key regulator of plasma lipid levels. Human apoE exists as three common isoforms and the parent form, apoE3, operates optimally in promoting clearance of triglyceride (TG)‐rich lipoproteins and is associated with normal plasma lipid levels. This result occurs because apoE3 possesses both the requisite lipid‐binding ability and affinity for the low density lipoprotein receptor (LDLR) to mediate appropriate lipolytic processing and endocytosis of TG‐rich lipoprotein remnant particles. ApoE2 which differs from apoE3 by the single amino acid substitution Arg158Cys located near the LDLR recognition site exhibits impaired binding to the receptor and an inability to promote clearance of TG‐rich lipoprotein remnant particles; this isoform is associated with Type‐III hyperlipoproteinemia. ApoE4 which differs from apoE3 by the single amino acid substitution Cys112Arg is also associated with dyslipidemia although binding of this isoform to the LDLR is unaffected. The amino acid substitution affects the organization and stability of both the N‐terminal helix bundle domain and separately folded C‐terminal domain so that apoE4 has enhanced lipid binding ability. As a consequence, apoE4 binds better than apoE3 to the surface of very low density lipoprotein (VLDL) particles and impairs their lipolytic processing in the circulation so that apoE4 is associated with a more pro‐atherogenic lipoprotein‐cholesterol distribution (higher VLDL‐cholesterol/high density lipoprotein‐cholesterol ratio). This review summarizes current understanding of the structural differences between apoE2, apoE3, and apoE4, and the molecular mechanisms responsible for the alterations in lipoprotein metabolism resulting from this polymorphism of apoE. Detailed knowledge of how expression of structurally distinct apoE variants modifies lipoprotein metabolism provides a basis for developing ways to manipulate the functionality of apoE in vivo. © 2014 IUBMB Life, 66(9):616–623, 2014
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“This is attributed to the fact that the cysteine change at position 158 in APOE2, near the LDLR binding region, hinders APOE2 binding to the LDLR [30, 40].”
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“As a result, apoE4 binds better and is more abundant on the surface of VLDL and chylomicron particles than apoE3 or apoE2 19).”
From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [19]
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Cites
Apolipoprotein E polymorphism and atherosclerosis.
Davignon, J., Gregg, R. E., & Sing, C. F. (1988) · Arteriosclerosis: An Official Journal of the American Heart Association, Inc. · doi:10.1161/01.atv.8.1.1 · Cited by 1,981
Segrest, J., Jones, M., Loof, H. D., Brouillette, C. G., Venkatachalapathi, Y. V., & Anantharamaiah, G. M. (1992) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)41536-6 · Cited by 868
Apolipoprotein E: Structure-Function Relationships
Weisgraber, K. H. (1994) · Advances in Protein Chemistry · doi:10.1016/s0065-3233(08)60642-7 · Cited by 830
Mahley, R. W., & Ji, Z.-S. (1999) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)33334-4 · Cited by 693
Weisgraber, K. H., Innerarity, T. L., & Mahley, R. W. (1982) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)34954-8 · Cited by 673
Apolipoprotein E structure: insights into function
Hatters, D. M., Peters-Libeu, C. A., & Weisgraber, K. H. (2006) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2006.06.008 · Cited by 583 · cited 1×
“The latter interaction occurs in quasi-spherical apoE/dipalmitoyl phosphatidylcholine particles where the two apoE molecules adopt a horseshoe shape (7,26).”
BackgroundApolipoprotein E: structure determines function, from atherosclerosis to Alzheimer's disease to AIDS
Mahley, R. W., Weisgraber, K. H., & Huang, Y. (2009) · Journal of Lipid Research · doi:10.1194/jlr.r800069-jlr200 · Cited by 580
Mahley, R. W., Huang, Y., & Rall, S. C. (1999) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)32417-2 · Cited by 447
Apo E structure determines VLDL clearance and atherosclerosis risk in mice
Knouff, C., Hinsdale, M. E., Mezdour, H., Altenburg, M. K., Watanabe, M., Quarfordt, S. H., Sullivan, P. M., & Maeda, N. (1999) · Journal of Clinical Investigation · doi:10.1172/jci6172 · Cited by 324
Dong, L. M., Wilson, C., Wardell, M. R., Simmons, T., Mahley, R. W., Weisgraber, K. H., & Agard, D. A. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)31797-0 · Cited by 320
Apolipoprotein E: From lipid transport to neurobiology
Hauser, P. S., Narayanaswami, V., & Ryan, R. O. (2011) · Progress in Lipid Research · doi:10.1016/j.plipres.2010.09.001 · Cited by 320
Apoprotein E as a lipid transport and signaling protein in the blood, liver, and artery wall
Getz, G. S., & Reardon, C. A. (2009) · Journal of Lipid Research · doi:10.1194/jlr.r800058-jlr200 · Cited by 319
Human Apolipoprotein E4 Domain Interaction
Dong, L.-M., & Weisgraber, K. H. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.32.19053 · Cited by 318
Morrow, J. A., Segall, M. L., Lund-Katz, S., Phillips, M. C., Knapp, M., Rupp, B., & Weisgraber, K. H. (2000) · Biochemistry · doi:10.1021/bi000099m · Cited by 315
Self-citationWeisgraber, K. H. (1990) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)42621-5 · Cited by 304
Bellosta, S., Mahley, R. W., Sanan, D. A., Murata, J., Newland, D. L., Taylor, J. M., & Pitas, R. E. (1995) · Journal of Clinical Investigation · doi:10.1172/jci118271 · Cited by 284
Topology of human apolipoprotein E3 uniquely regulates its diverse biological functions
Chen, J., Li, Q., & Wang, J. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1106420108 · Cited by 283
Weisgraber, K. H., Mahley, R. W., Kowal, R. C., Herz, J., Goldstein, J. L., & Brown, M. S. (1990) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)45726-2 · Cited by 235
Saito, H., Lund‐Katz, S., & Phillips, M. C. (2004) · Progress in Lipid Research · doi:10.1016/j.plipres.2004.05.002 · Cited by 219
Self-citationApolipoprotein E and atherosclerosis: insight from animal and human studies
Davignon, J., Cohn, J. S., Mabile, L., & Bernier, L. (1999) · Clinica Chimica Acta · doi:10.1016/s0009-8981(99)00097-2 · Cited by 210
Apolipoprotein E4 Forms a Molten Globule
Morrow, J. A., Hatters, D. M., Lu, B., Höchtl, P., Oberg, K. A., Rupp, B., & Weisgraber, K. H. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m204898200 · Cited by 204
Overexpression and Accumulation of Apolipoprotein E as a Cause of Hypertriglyceridemia
Huang, Y., Liu, X. Q., Rall, S. C., Taylor, J. M., von Eckardstein, A., Assmann, G., & Mahley, R. W. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.41.26388 · Cited by 204
Domain Structure and Lipid Interaction in Human Apolipoproteins A-I and E, a General Model
Saito, H., Dhanasekaran, P., Nguyen, D., Holvoet, P., Lund‐Katz, S., & Phillips, M. C. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m303365200 · Cited by 179
Self-citationBradley, W. A., Hwang, S. L., Karlin, J. B., Lin, A. H., Prasad, S. C., Gotto, A. M., & Gianturco, S. H. (1984) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)42663-9 · Cited by 166
Westerlund, J. A., & Weisgraber, K. H. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)82318-3 · Cited by 164
Apolipoprotein E knock-out and knock-in mice: atherosclerosis, metabolic syndrome, and beyond
Pendse, A. A., Arbones-Mainar, J. M., Johnson, L. A., Altenburg, M. K., & Maeda, N. (2009) · Journal of Lipid Research · doi:10.1194/jlr.r800070-jlr200 · Cited by 155
Molecular basis of exchangeable apolipoprotein function
Narayanaswami, V., & Ryan, R. O. (2000) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/s1388-1981(99)00176-6 · Cited by 152
Rensen, P. C. N., & van Berkel, T. J. C. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.25.14791 · Cited by 144
Novel mechanism for defective receptor binding of apolipoprotein E2 in type III hyperlipoproteinemia
Dong, L., Parkin, S., Trakhanov, S. D., Rupp, B., Simmons, T., Arnold, K. S., Newhouse, Y. M., Innerarity, T. L., & Weisgraber, K. H. (1996) · Nature Structural & Molecular Biology · doi:10.1038/nsb0896-718 · Cited by 129
Apolipoprotein E Recycling: Implications for Dyslipidemia and Atherosclerosis
Heeren, J., Beisiegel, U., & Grewal, T. (2006) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/01.atv.0000201282.64751.47 · Cited by 123
Lipid Binding-induced Conformational Change in Human Apolipoprotein E
Saito, H., Dhanasekaran, P., Baldwin, F., Weisgraber, K. H., Lund-Katz, S., & Phillips, M. C. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m106337200 · Cited by 113
Self-citationNew Insights into the Heparan Sulfate Proteoglycan-binding Activity of Apolipoprotein E
Libeu, C. P., Lund-Katz, S., Phillips, M. C., Wehrli, S., Hernáiz, M. J., Capila, I., Linhardt, R. J., Raffaı̈, R. L., Newhouse, Y. M., Zhou, F., et al. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m104746200 · Cited by 113
Self-citationDifferential distribution of apolipoprotein E isoforms in human plasma lipoproteins
Steinmetz, A., Jakobs, C., Motzny, S., & Kaffarnik, H. (1989) · Arteriosclerosis: An Official Journal of the American Heart Association, Inc. · doi:10.1161/01.atv.9.3.405 · Cited by 93
Two-step Mechanism of Binding of Apolipoprotein E to Heparin
Futamura, M., Dhanasekaran, P., Handa, T., Phillips, M. C., Lund-Katz, S., & Saito, H. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m411719200 · Cited by 91
Self-citationLu, B., Morrow, J. A., & Weisgraber, K. H. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m003508200 · Cited by 89
Effects of Polymorphism on the Lipid Interaction of Human Apolipoprotein E
Saito, H., Dhanasekaran, P., Baldwin, F., Weisgraber, K. H., Phillips, M. C., & Lund-Katz, S. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m304814200 · Cited by 89
Self-citationNguyen, D., Dhanasekaran, P., Nickel, M., Nakatani, R., Saito, H., Phillips, M. C., & Lund-Katz, S. (2010) · Biochemistry · doi:10.1021/bi1017655 · Cited by 89
Self-citationModulation of Apolipoprotein E Structure by Domain Interaction
Hatters, D. M., Budamagunta, M. S., Voss, J. C., & Weisgraber, K. H. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m506044200 · Cited by 88
Fisher, C. A., Narayanaswami, V., & Ryan, R. O. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m002643200 · Cited by 78
Zaiou, M., Arnold, K. S., Newhouse, Y. M., Innerarity, T. L., Weisgraber, K. H., Segall, M. L., Phillips, M. C., & Lund‐Katz, S. (2000) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)32014-9 · Cited by 77
Self-citationNarayanaswami, V., Maiorano, J. N., Dhanasekaran, P., Ryan, R. O., Phillips, M. C., Lund‐Katz, S., & Davidson, W. S. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m313318200 · Cited by 77
Self-citationProbing the pathways of chylomicron and HDL metabolism using adenovirus-mediated gene transfer
Zannis, V. I., Chroni, A., Kypreos, K. E., Kan, H.-Y., Cesar, T. B., Zanni, E. E., & Kardassis, D. (2004) · Current Opinion in Lipidology · doi:10.1097/00041433-200404000-00008 · Cited by 74
Li, H., Dhanasekaran, P., Alexander, E. T., Rader, D. J., Phillips, M. C., & Lund‐Katz, S. (2013) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.112.301193 · Cited by 73
Self-citationEffect of Arginine 172 on the Binding of Apolipoprotein E to the Low Density Lipoprotein Receptor
Morrow, J. A., Arnold, K. S., Dong, J., Balestra, M. E., Innerarity, T. L., & Weisgraber, K. H. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.4.2576 · Cited by 67
Molecular Mechanism of Apolipoprotein E Binding to Lipoprotein Particles
Nguyen, D., Dhanasekaran, P., Phillips, M. C., & Lund‐Katz, S. (2009) · Biochemistry · doi:10.1021/bi9000694 · Cited by 66
Self-citationIntrahepatic Role of Exchangeable Apolipoproteins in Lipoprotein Assembly and Secretion
Sundaram, M., & Yao, Z. (2012) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.111.241455 · Cited by 62
Lipid Association-induced N- and C-terminal Domain Reorganization in Human Apolipoprotein E3
Narayanaswami, V., Szeto, S. S. W., & Ryan, R. O. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m102953200 · Cited by 59
Garai, K., Baban, B., & Frieden, C. (2011) · Biochemistry · doi:10.1021/bi1020106 · Cited by 57
Sakamoto, T., Tanaka, M., Vedhachalam, C., Nickel, M., Nguyen, D., Dhanasekaran, P., Phillips, M. C., Lund-Katz, S., & Saito, H. (2008) · Biochemistry · doi:10.1021/bi701923h · Cited by 54
Self-citationEffects of Lipid Interaction on the Lysine Microenvironments in Apolipoprotein E
Lund‐Katz, S., Zaiou, M., Wehrli, S. L., Dhanasekaran, P., Baldwin, F., Weisgraber, K. H., & Phillips, M. C. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m005265200 · Cited by 54
Self-citationApolipoprotein E•dipalmitoylphosphatidylcholine particles are ellipsoidal in solution
Peters-Libeu, C. A., Newhouse, Y. M., Hall, S. C., Witkowska, H. E., & Weisgraber, K. H. (2007) · Journal of Lipid Research · doi:10.1194/jlr.m600545-jlr200 · Cited by 54
Kitajima, K., Marchadier, D. H. L., Miller, G. C., Gao, G.-P., Wilson, J. M., & Rader, D. J. (2006) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/01.atv.0000231520.26490.54 · Cited by 54
Structural Analysis of Lipoprotein E Particles
Schneeweis, L. A., Koppaka, V., Lund-Katz, S., Phillips, M. C., & Axelsen, P. H. (2005) · Biochemistry · doi:10.1021/bi050872j · Cited by 39
Self-citationConcerning the structure of apoE
Frieden, C., & Garai, K. (2013) · Protein Science · doi:10.1002/pro.2379 · Cited by 39
Examination of Lipid-bound Conformation of Apolipoprotein E4 by Pyrene Excimer Fluorescence
Drury, J., & Narayanaswami, V. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m414019200 · Cited by 37
Mann, W. A., Meyer, N., Weber, W., Meyer, S., Greten, H., & Beisiegel, U. (1995) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)39885-0 · Cited by 37
Gupta, V., Narayanaswami, V., Budamagunta, M. S., Yamamato, T., Voss, J. C., & Ryan, R. O. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m608085200 · Cited by 32
Nguyen, D., Dhanasekaran, P., Nickel, M., Mizuguchi, C., Watanabe, M., Saito, H., Phillips, M. C., & Lund-Katz, S. (2014) · Biochemistry · doi:10.1021/bi500340z · Cited by 30
Self-citationDong, L., Innerarity, T. L., Arnold, K. S., Newhouse, Y. M., & Weisgraber, K. H. (1998) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)32541-4 · Cited by 26
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Metadata
- Authors
- Phillips, M. C.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Phillips, Michael C.
- ORCID
- Phillips, Michael C.
- Venue
- IUBMB Life
- Publisher
- Wiley
- Published
- 2014-09
- Volume
- 66
- Issue
- 9
- Pages
- 616-623
- ISSN
- 1521-6543 (ISSN-L)
- 1521-6551
- OpenAlex
- W1841798962
- Cited by
- 328
- References
- 59
- Citations by year
- 2026: 20 · 2025: 25 · 2024: 41 · 2023: 35 · 2022: 36 · 2021: 38 · 2020: 27 · 2019: 27 · 2018: 24 · 2017: 23 · 2016: 22 · 2015: 8
- FWCI
- 2.85
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- IUBMB Life (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Keywords
- apolipoprotein E, apolipoprotein E isoforms, apolipoprotein E2, apolipoprotein E3, APOE ε4, lipoprotein metabolism, LDL receptor binding, type III hyperlipoproteinemia, dyslipidemia, VLDL cholesterol, protein structure, lipid binding, genetic polymorphism
- MeSH terms
- Apolipoproteins E, Humans, Lipoproteins, Models, Molecular, Protein Binding, Amino Acid Substitution, Protein Isoforms, Lipid Metabolism Disorders
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