The DOI matches its Crossref record; 59 of the 59 references it cites were found in a registry or an index.
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
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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].”
In the citing paper
“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]
Citations
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
Cited by
Sorted by citations
Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies
Yamazaki, Y., Zhao, N., Caulfield, T. R., Liu, C.-C., & Bu, G. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0228-7 · Cited by 1,425
Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease
Guo, T., Zhang, D., Zeng, Y., Huang, T. Y., Xu, H., & Zhao, Y. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00391-7 · Cited by 994
Epidemiology, Risk Factors, and Clinical Features of Intracerebral Hemorrhage: An Update
An, S. J., Kim, T. J., & Yoon, B. W. (2017) · Journal of Stroke · doi:10.5853/jos.2016.00864 · Cited by 1,049
Lipids and Alzheimer’s Disease
Kao, Y.-C., Ho, P.-C., Tu, Y.-K., Jou, I.-M., & Tsai, K.-J. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21041505 · Cited by 485
Transcriptional signature in microglia associated with Aβ plaque phagocytosis
Grubman, A., Choo, X. Y., Chew, G., Ouyang, J. F., Sun, G., Croft, N. P., Rossello, F. J., Simmons, R., Buckberry, S., Landin, D. V., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-23111-1 · Cited by 357
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
