Apolipoprotein E: Cholesterol Transport Protein with Expanding Role in Cell Biology
Abstract
Apolipoprotein E is a plasma protein that serves as a ligand for low density lipoprotein receptors and, through its interaction with these receptors, participates in the transport of cholesterol and other lipids among various cells of the body. A mutant form of apolipoprotein E that is defective in binding to low density lipoprotein receptors is associated with familial type III hyperlipoproteinemia, a genetic disorder characterized by elevated plasma cholesterol levels and accelerated coronary artery disease. Apolipoprotein E is synthesized in various organs, including liver, brain, spleen, and kidney, and is present in high concentrations in interstitial fluid, where it appears to participate in cholesterol redistribution from cells with excess cholesterol to those requiring cholesterol. Apolipoprotein E also appears to be involved in the repair response to tissue injury; for example, markedly increased amounts of apolipoprotein E are found at sites of peripheral nerve injury and regeneration. Other functions of apolipoprotein E, unrelated to lipid transport, are becoming known, including immunoregulation and modulation of cell growth and differentiation.
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APOE2 homozygosity can lead to Hyperlipoproteinemia type III (HLP), characterized by mixed hypercholesterolemia and hypertriglyceridemia.
“The critical role of APOE in lipid metabolism is underscored by evidence showing that APOE2 homozygosity can lead to Hyperlipoproteinemia type III (HLP), characterized by mixed hypercholesterolemia and hypertriglyceridemia [35–39].”
APOE2hAβ rats are characterized as a model for type III HLP.
“This observation, coupled with evident mixed hypercholesterolemia and hypertriglyceridemia, supports the characterization of APOE2hAβ rats as a model for type III HLP”
ApoE is a crucial factor in development of AD.
“ApoE is also a crucial factor in the development of AD (5, 6, 31, 32).”
From The E3 ubiquitin ligase Idol controls brain LDL receptor expression, ApoE clearance, and Aβ amyloidosis (2015) · cites this paper as [5]
The APOE gene is a known genetic risk factor for neurodegeneration and cardiovascular disease.
“The APOE gene is a known genetic risk factor for neurodegeneration and cardiovascular disease (CVD) [1, 2].”
From Characterization of APOE Christchurch carriers in 455,306 UK Biobank participants (2023) · cites this paper as [1]
Each APOE allele encodes an apoE proteoform: apoE ɛ2 has two cysteine residues, apoE ɛ3 has C158R, and apoE ɛ4 has C112R/C158R.
“Each allele encodes for an apoE proteoform where two cysteine residues are present in apoE ɛ2, or mutated to arginine C158R in apoE ɛ3, or C112R/C158R in apoE ɛ4 [3].”
From Discovery of a Missense Mutation (Q222K) of the <i>APOE</i> Gene from the Australian Imaging, Biomarker and Lifestyle Study (2023) · cites this paper as [3]
apoE on triglyceride-rich lipoproteins binds to LDLR, LRP1, and HSPGs.
“apoE on triglyceride-rich lipoproteins binds to the LDL receptor (LDLR), the LDLR-related protein 1 (LRP1), and heparan sulfate proteoglycans (HSPGs) ( 3,4 ).”
From Macrophage-derived apoESendai suppresses atherosclerosis while causing lipoprotein glomerulopathy in hyperlipidemic mice (2014) · cites this paper as [3]
apoE made by macrophages is secreted into the circulation, where it associates with lipoproteins and mediates their hepatic uptake by the liver.
“apoE made by macrophages is secreted into the circulation, where it associates with lipoproteins and mediates their hepatic uptake by the liver ( 3,6 ).”
From Macrophage-derived apoESendai suppresses atherosclerosis while causing lipoprotein glomerulopathy in hyperlipidemic mice (2014) · cites this paper as [3]
Macrophage apoE effects manifest as secretion into the circulation and association with lipoproteins to mediate their hepatic uptake.
“Atherogenesis is infl uenced by macrophage expression of apoE ( 11 ), the effects of which manifest as: 1 ) secretion into the circulation and association with lipoproteins to mediate their hepatic uptake ( 3, 6 ); and 2 ) modulation of the macrophage infl ammatory response in the atheroma ( 16,17 ).”
From Macrophage-derived apoESendai suppresses atherosclerosis while causing lipoprotein glomerulopathy in hyperlipidemic mice (2014) · cites this paper as [3]
ApoE4 differs from apoE3 by a single amino acid.
“ApoE4 differs from apoE3 by a single amino acid [15]”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [15]
The single amino acid difference alters the intramolecular interactions in apoE4.
“which alters the intramolecular interactions in apoE4”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [15]
Apolipoprotein E (apoE) is a critical ligand for high-affinity binding of remnant lipoproteins to members of the low density lipoprotein receptor (LDLR) family and HSPG.
“Apolipoprotein E (apoE) is a critical ligand for high-affinity binding of remnant lipoproteins to members of the low density lipoprotein receptor (LDLR) family and HSPG (5–7).”
From Role of the N- and C-Terminal Domains in Binding of Apolipoprotein E Isoforms to Heparan Sulfate and Dermatan Sulfate: A Surface Plasmon Resonance Study (2008) · cites this paper as [5]
The percentage of e4 homozygotes in the sample of 235 volunteers with a family history of probable Alzheimer's disease was higher than in the general population (5.1 percent vs. 2 to 3 percent).
“The percentage of e 4 homozygotes in this sample was higher than that in the general population (5.1 percent vs. 2 to 3 percent), 8”
From Preclinical Evidence of Alzheimer's Disease in Persons Homozygous for the ε4 Allele for Apolipoprotein E (1996) · cites this paper as [8]
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References 125 · Cited by 4,028
- Authors
- Mahley, R. W.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Mahley, Robert W.
- ORCID
- Mahley, Robert W.
- Venue
- Science
- Published
- 1988-04-29
- Volume
- 240
- Issue
- 4852
- Pages
- 622-630
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2034968148
- Cited by
- 4,028
- References
- 125
- Citations by year
- 2026: 50 · 2025: 57 · 2024: 73 · 2023: 73 · 2022: 83 · 2021: 69 · 2020: 94 · 2019: 91 · 2018: 89 · 2017: 82 · 2016: 96 · 2015: 103 · 2014: 113 · 2013: 115 · 2012: 103
- FWCI
- 21.33
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- apolipoprotein E, LDL receptor, cholesterol transport, lipid transport, type III hyperlipoproteinemia, coronary artery disease, interstitial fluid, tissue repair, peripheral nerve regeneration, immune regulation, cell growth and differentiation
- MeSH terms
- Amino Acid Sequence, Apolipoproteins E, Biological Transport, Cholesterol, Gene Expression Regulation, Humans, Hyperlipoproteinemia Type III, Immunity, Molecular Sequence Data, Polymorphism, Genetic, Protein Conformation, Receptors, LDL, Lipid Metabolism
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