Apolipoprotein E

Apolipoprotein E
PDB rendering based on 1b68.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1B68​, 1BZ4​, 1EA8​, 1GS9​, 1H7I​, 1LE2​, 1LE4​, 1LPE​, 1NFN​, 1NFO​, 1OEF​, 1OEG​, 1OR2​, 1OR3​, 2KC3​, 2KNY​, 2L7B​
Identifiers
Symbols	APOE ; AD2; APO-E; LDLCQ5; LPG
External IDs	OMIM: 107741 MGI: 88057 HomoloGene: 30951 GeneCards: APOE Gene
Gene ontology Molecular function • beta-amyloid binding • lipid transporter activity • protein binding • phospholipid binding • heparin binding • lipid binding • cholesterol binding • antioxidant activity • cholesterol transporter activity • identical protein binding • protein homodimerization activity • metal chelating activity • tau protein binding • low-density lipoprotein particle receptor binding • phosphatidylcholine-sterol O-acyltransferase activator activity • very-low-density lipoprotein particle receptor binding • lipoprotein particle binding Cellular component • extracellular region • extracellular space • nucleus • cytoplasm • early endosome • endoplasmic reticulum • Golgi apparatus • plasma membrane • membrane • dendrite • extracellular matrix • very-low-density lipoprotein particle • low-density lipoprotein particle • intermediate-density lipoprotein particle • high-density lipoprotein particle • chylomicron • neuronal cell body • extracellular exosome • endocytic vesicle lumen • blood microparticle • extracellular vesicle Biological process • response to reactive oxygen species • retinoid metabolic process • negative regulation of endothelial cell proliferation • response to dietary excess • triglyceride metabolic process • cholesterol biosynthetic process • cholesterol catabolic process • cellular calcium ion homeostasis • receptor-mediated endocytosis • cytoskeleton organization • G-protein coupled receptor signaling pathway • nitric oxide mediated signal transduction • synaptic transmission, cholinergic • phototransduction, visible light • cholesterol metabolic process • regulation of gene expression • negative regulation of platelet activation • positive regulation of cholesterol esterification • positive regulation of cholesterol efflux • long-chain fatty acid transport • protein import • virion assembly • triglyceride catabolic process • cGMP-mediated signaling • negative regulation of blood coagulation • regulation of axon extension • positive regulation of cGMP biosynthetic process • neuron projection regeneration • regulation of Cdc42 protein signal transduction • positive regulation of low-density lipoprotein particle receptor catabolic process • cholesterol efflux • phospholipid efflux • very-low-density lipoprotein particle remodeling • low-density lipoprotein particle remodeling • high-density lipoprotein particle remodeling • high-density lipoprotein particle assembly • chylomicron remnant clearance • high-density lipoprotein particle clearance • very-low-density lipoprotein particle clearance • lipoprotein metabolic process • lipoprotein biosynthetic process • lipoprotein catabolic process • vasodilation • cholesterol homeostasis • negative regulation of MAP kinase activity • negative regulation of neuron apoptotic process • negative regulation of blood vessel endothelial cell migration • reverse cholesterol transport • small molecule metabolic process • positive regulation by host of viral process • negative regulation of cholesterol biosynthetic process • positive regulation of lipid biosynthetic process • intracellular transport • regulation of neuronal synaptic plasticity • artery morphogenesis • negative regulation of inflammatory response • positive regulation of nitric-oxide synthase activity • positive regulation of membrane protein ectodomain proteolysis • negative regulation of lipid biosynthetic process • maintenance of location in cell • fatty acid homeostasis • positive regulation of dendritic spine development • negative regulation of dendritic spine development • negative regulation of cholesterol efflux • alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate selective glutamate receptor clustering • N-methyl-D-aspartate receptor clustering • regulation of beta-amyloid clearance • regulation of neuron death • negative regulation of neuron death • positive regulation of neuron death • negative regulation of postsynaptic membrane organization • positive regulation of postsynaptic membrane organization • negative regulation of presynaptic membrane organization • positive regulation of presynaptic membrane organization • positive regulation of beta-amyloid formation • negative regulation of beta-amyloid formation • regulation of tau-protein kinase activity • negative regulation of dendritic spine maintenance • positive regulation of dendritic spine maintenance • positive regulation of phospholipid efflux • positive regulation of neurofibrillary tangle assembly • negative regulation of phospholipid efflux • negative regulation of lipid transport across blood brain barrier • positive regulation of lipid transport across blood brain barrier Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	348	11816
Ensembl	ENSG00000130203	ENSMUSG00000002985
UniProt	P02649	P08226
RefSeq (mRNA)	NM_000041	NM_001305819
RefSeq (protein)	NP_000032	NP_001292748
Location (UCSC)	Chr 19: 44.91 – 44.91 Mb	Chr 7: 19.7 – 19.7 Mb
PubMed search

Apolipoprotein E (APOE) is a class of apolipoprotein found in the chylomicron and Intermediate-density lipoprotein (IDLs) that is essential for the normal catabolism of triglyceride-rich lipoprotein constituents.^[1] In peripheral tissues, APOE is primarily produced by the liver and macrophages, and mediates cholesterol metabolism in an isoform-dependent manner. In the central nervous system, APOE is mainly produced by astrocytes, and transports cholesterol to neurons via APOE receptors, which are members of the low density lipoprotein receptor gene family.^[2] This protein is involved in Alzheimer’s disease and cardiovascular disease.^[3]

Structure

Gene

The gene, APOE, is mapped to chromosome 19 in a cluster with Apolipoprotein C1 and the Apolipoprotein C2. The APOE gene consists of four exons and three introns, totaling 3597 base pairs. APOE is transcriptionally activated by the liver X receptor (an important regulator of cholesterol, fatty acid, and glucose homeostasis) and peroxisome proliferator-activated receptor γ, nuclear receptors that form heterodimers with Retinoid X receptors.^[4] In melanocytic cells APOE gene expression may be regulated by MITF.^[5]

Protein

APOE is 299 amino acids long and contains multiple amphipathic α-helices. According to crystallography studies, a hinge region connects the N- and C-terminal regions of the protein. The N-terminal region (residues 1–167) forms an anti-parallel four-helix bundle such that the non-polar sides face inside the protein. Meanwhile, the C-terminal domain (residues 206-299) contains three α-helices which form a large exposed hydrophobic surface and interact with those in the N-terminal helix bundle domain through hydrogen bonds and salt-bridges. The C-terminal region also contains a low density lipoprotein receptor (LDLR)-binding site.^[6]

Polymorphisms

APOE is polymorphic,^[7][8] with three major alleles: ApoE2 (cys112, cys158), ApoE3 (cys112, arg158), and ApoE4 (arg112, arg158).^[3][9][10] Although these allelic forms differ from each other by only one or two amino acids at positions 112 and 158,^[11][12][13] these differences alter APOE structure and function. These have physiological consequences:

• E2 (rs7412-T, rs429358-T) has an allele frequency of approximately 7 percent.^[14] This variant of the apoprotein binds poorly to cell surface receptors while E3 and E4 bind well.^[15] E2 is associated with both increased and decreased risk for atherosclerosis. Individuals with an E2/E2 combination may clear dietary fat slowly and be at greater risk for early vascular disease and the genetic disorder type III hyperlipoproteinemia—94.4% of such patients are E2/E2, while only ∼2% of E2/E2 develop the disease, so other environmental and genetic factors are likely to be involved (such as cholesterol in the diet and age).^[16][17][18] E2 has also been implicated in Parkinson's disease,^[19] but this finding was not replicated in a larger population association study.^[20]
• E3 (rs7412-C, rs429358-T) has an allele frequency of approximately 79 percent.^[14] It is considered the "neutral" Apo E genotype.
• E4 (rs7412-C, rs429358-C) has an allele frequency of approximately 14 percent.^[14] E4 has been implicated in atherosclerosis,^[21] Alzheimer's disease,^[22][23] impaired cognitive function,^[24][25] reduced hippocampal volume,^[25] HIV,^[26] faster disease progression in multiple sclerosis,^[27][28] unfavorable outcome after traumatic brain injury,^[29] ischemic cerebrovascular disease,^[30] sleep apnea,^[31][32] accelerated telomere shortening ^[33] and reduced neurite outgrowth.^[34] A notable advantage of the E4 allele (relative to E2 and E3) is a positive association with higher levels of vitamin D, which may help explain its prevalence despite its seeming complicity in various diseases or disorders.^[35]

However, there is much to be learned about these APOE isoforms, including the interaction of other potentially protective genetic polymorphisms, so caution is advised before making determinant statements about the influence of APOE polymorphisms; this is particularly true as it relates to how APOE isoforms influence cognition and the development of Alzheimer’s Disease. In addition, there is no evidence that APOE polymorphisms influence cognition in younger age groups (other than possible increased episodic memory ability and neural efficiency in younger APOE4 age groups), nor is there evidence that the APOE4 isoform places individuals at increased risk for any infectious disease.^[36]

Function

APOE transports lipoproteins, fat-soluble vitamins, and cholesterol into the lymph system and then into the blood. It is synthesized principally in the liver, but has also been found in other tissues such as the brain, kidneys, and spleen.^[9] In the nervous system, non-neuronal cell types, most notably astroglia and microglia, are the primary producers of APOE, while neurons preferentially express the receptors for APOE.^[37] There are seven currently identified mammalian receptors for APOE which belong to the evolutionarily conserved LDLR family.^[38]

APOE was initially recognized for its importance in lipoprotein metabolism and cardiovascular disease. Defects in APOE result in familial dysbetalipoproteinemia aka type III hyperlipoproteinemia (HLP III), in which increased plasma cholesterol and triglycerides are the consequence of impaired clearance of chylomicron, VLDL and LDL remnants.^[1] More recently, it has been studied for its role in several biological processes not directly related to lipoprotein transport, including Alzheimer's disease (AD), immunoregulation, and cognition.^[3] Though the exact mechanisms remain to be elucidated, isoform 4 of APOE, encoded by an APOE allele, has been associated with increased calcium ion levels and apoptosis following mechanical injury.^[39]

In the field of immune regulation, a growing number of studies point to APOE's interaction with many immunological processes, including suppressing T cell proliferation, macrophage functioning regulation, lipid antigen presentation facilitation (by CD1) ^[40] to natural killer T cell as well as modulation of inflammation and oxidation.^[41] APOE is produced by macrophages and APOE secretion has been shown to be restricted to classical monocytes in PBMC, and the secretion of APOE by monocytes is down regulated by inflammatory cytokines and upregulated by TGF-beta.^[42]

Clinical Significance

Alzheimer's disease

The E4 variant is the largest known genetic risk factor for late-onset sporadic Alzheimer's disease (AD) in a variety of ethnic groups.^[43] Caucasian and Japanese carriers of 2 E4 alleles have between 10 and 30 times the risk of developing AD by 75 years of age, as compared to those not carrying any E4 alleles. While the exact mechanism of how E4 causes such dramatic effects remains to be fully determined, evidence has been presented suggesting an interaction with amyloid.^[44] Alzheimer's disease is characterized by build-ups of aggregates of the peptide beta-amyloid. Apolipoprotein E enhances proteolytic break-down of this peptide, both within and between cells. The isoform ApoE-ε4 is not as effective as the others at promoting these reactions, resulting in increased vulnerability to AD in individuals with that gene variation.^[45]

The pivotal role of ApoE in AD was first identified through linkage analysis by Margaret Pericak-Vance^[46] while working in the Roses lab at Duke University^[47] Linkage studies were followed by association analysis confirming the role of the ApoE4 allele as a strong genetic risk factor for AD.^[22][23]

Although 40-65% of AD patients have at least one copy of the ε4 allele, ApoE4 is not a determinant of the disease - at least a third of patients with AD are ApoE4 negative and some ApoE4 homozygotes never develop the disease. Yet those with two ε4 alleles have up to 20 times the risk of developing AD.^[48] There is also evidence that the ApoE2 allele may serve a protective role in AD.^[49] Thus, the genotype most at risk for Alzheimer's disease and at an earlier age is ApoE 4,4. Using genotype ApoE 3,3 as a benchmark (with the persons who have this genotype regarded as having a risk level of 1.0), individuals with genotype ApoE4,4 have an odds ratio of 14.9 of developing Alzheimer's disease. Individuals with the ApoE 3,4 genotype face an odds ratio of 3.2, and people with a copy of the 2 allele and the 4 allele (ApoE2,4), have an odds ratio of 2.6. Persons with one copy each of the 2 allele and the 3 allele (ApoE2,3) have an odds ratio of 0.6. Persons with two copies of the 2 allele (ApoE2,2) also have an odds ratio of 0.6.^[50]

Estimated worldwide human allele frequencies of ApoE * in Caucasian population[50]
Allele	ε2	ε3	ε4
General Frequency	8.4%	77.9%	13.7%
AD Frequency	3.9%	59.4%	36.7%

Atherosclerosis

Knockout mice that lack the apolipoprotein-E gene (ApoE⁻/⁻) develop extreme hypercholesterolemia when fed a high-fat diet.^[51]

Interactions

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles. ^{[§ 1]}

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Statin Pathway edit

1. The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430".

References

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Further reading

• Liu CC, Liu CC, Kanekiyo T, Xu H, Bu G (Feb 2013). "Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy". Nature Reviews. Neurology 9 (2): 106–18. doi:10.1038/nrneurol.2012.263. PMID 23296339.
• Gunzburg MJ, Perugini MA, Howlett GJ (Dec 2007). "Structural basis for the recognition and cross-linking of amyloid fibrils by human apolipoprotein E". The Journal of Biological Chemistry 282 (49): 35831–41. doi:10.1074/jbc.M706425200. PMID 17916554.
• Kolovou GD, Anagnostopoulou KK (Aug 2007). "Apolipoprotein E polymorphism, age and coronary heart disease". Ageing Research Reviews 6 (2): 94–108. doi:10.1016/j.arr.2006.11.001. PMID 17224309.
• Lambert JC, Amouyel P (Aug 2007). "Genetic heterogeneity of Alzheimer's disease: complexity and advances". Psychoneuroendocrinology. 32 Suppl 1: S62–70. doi:10.1016/j.psyneuen.2007.05.015. PMID 17659844.
• Raber J (2007). "Role of apolipoprotein E in anxiety". Neural Plasticity 2007: 91236. doi:10.1155/2007/91236. PMC: 1940061. PMID 17710250.
• Ye J (Aug 2007). "Reliance of host cholesterol metabolic pathways for the life cycle of hepatitis C virus". PLoS Pathogens 3 (8): e108. doi:10.1371/journal.ppat.0030108. PMC: 1959368. PMID 17784784.
• Bennet AM, Di Angelantonio E, Ye Z, Wensley F, Dahlin A, Ahlbom A, Keavney B, Collins R, Wiman B, de Faire U, Danesh J (Sep 2007). "Association of apolipoprotein E genotypes with lipid levels and coronary risk". JAMA 298 (11): 1300–11. doi:10.1001/jama.298.11.1300. PMID 17878422.
• Itzhaki RF, Dobson CB, Shipley SJ, Wozniak MA (Jun 2004). "The role of viruses and of APOE in dementia". Annals of the New York Academy of Sciences 1019 (1): 15–8. doi:10.1196/annals.1297.003. PMID 15246985.
• Ashford JW (2004). "APOE genotype effects on Alzheimer's disease onset and epidemiology". Journal of Molecular Neuroscience 23 (3): 157–65. doi:10.1385/JMN:23:3:157. PMID 15181244.
• Huang Y, Weisgraber KH, Mucke L, Mahley RW (2004). "Apolipoprotein E: diversity of cellular origins, structural and biophysical properties, and effects in Alzheimer's disease". Journal of Molecular Neuroscience 23 (3): 189–204. doi:10.1385/JMN:23:3:189. PMID 15181247.
• Masterman T, Hillert J (Jun 2004). "The telltale scan: APOE epsilon4 in multiple sclerosis". The Lancet. Neurology 3 (6): 331. doi:10.1016/S1474-4422(04)00763-X. PMID 15157846.
• Bocksch L, Stephens T, Lucas A, Singh B (Dec 2001). "Apolipoprotein E: possible therapeutic target for atherosclerosis". Current Drug Targets. Cardiovascular & Haematological Disorders 1 (2): 93–106. doi:10.2174/1568006013337944. PMID 12769659.
• Mahley RW, Rall SC (2002). "Apolipoprotein E: far more than a lipid transport protein". Annual Review of Genomics and Human Genetics 1 (1): 507–37. doi:10.1146/annurev.genom.1.1.507. PMID 11701639.
• Parasuraman R, Greenwood PM, Sunderland T (Apr 2002). "The apolipoprotein E gene, attention, and brain function". Neuropsychology 16 (2): 254–74. doi:10.1037/0894-4105.16.2.254. PMC: 1350934. PMID 11949718.
• Mahley RW, Ji ZS (Jan 1999). "Remnant lipoprotein metabolism: key pathways involving cell-surface heparan sulfate proteoglycans and apolipoprotein E". Journal of Lipid Research 40 (1): 1–16. PMID 9869645.
• Beffert U, Danik M, Krzywkowski P, Ramassamy C, Berrada F, Poirier J (Jul 1998). "The neurobiology of apolipoproteins and their receptors in the CNS and Alzheimer's disease". Brain Research. Brain Research Reviews 27 (2): 119–42. doi:10.1016/S0165-0173(98)00008-3. PMID 9622609.
• Roses AD, Einstein G, Gilbert J, Goedert M, Han SH, Huang D, Hulette C, Masliah E, Pericak-Vance MA, Saunders AM, Schmechel DE, Strittmatter WJ, Weisgraber KH, Xi PT (Jan 1996). "Morphological, biochemical, and genetic support for an apolipoprotein E effect on microtubular metabolism". Annals of the New York Academy of Sciences 777 (1): 146–57. doi:10.1111/j.1749-6632.1996.tb34413.x. PMID 8624078.
• Strittmatter WJ, Roses AD (May 1995). "Apolipoprotein E and Alzheimer disease". Proceedings of the National Academy of Sciences of the United States of America 92 (11): 4725–7. doi:10.1073/pnas.92.11.4725. PMC: 41779. PMID 7761390.
• de Knijff P, van den Maagdenberg AM, Frants RR, Havekes LM (1995). "Genetic heterogeneity of apolipoprotein E and its influence on plasma lipid and lipoprotein levels". Human Mutation 4 (3): 178–94. doi:10.1002/humu.1380040303. PMID 7833947.
• Moriyama K, Sasaki J, Matsunaga A, Arakawa F, Takada Y, Araki K, Kaneko S, Arakawa K (Sep 1992). "Apolipoprotein E1 Lys-146----Glu with type III hyperlipoproteinemia". Biochimica et Biophysica Acta 1128 (1): 58–64. doi:10.1016/0005-2760(92)90257-V. PMID 1356443.
• Mahley RW (Apr 1988). "Apolipoprotein E: cholesterol transport protein with expanding role in cell biology". Science 240 (4852): 622–30. doi:10.1126/science.3283935. PMID 3283935.
• Utermann G, Pruin N, Steinmetz A (Jan 1979). "Polymorphism of apolipoprotein E. III. Effect of a single polymorphic gene locus on plasma lipid levels in man". Clinical Genetics 15 (1): 63–72. doi:10.1111/j.1399-0004.1979.tb02028.x. PMID 759055.

External links

• Apolipoproteins E at the US National Library of Medicine Medical Subject Headings (MeSH)
• apoe4.info - website for APOE-epsilon-4 carriers