Apolipoprotein E

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Apolipoprotein E
PBB Protein APOE.jpg
PDB rendering based on 1b68.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols APOE ; AD2; APO-E; LDLCQ5; LPG
External IDs OMIM107741 MGI88057 HomoloGene30951 GeneCards: APOE Gene
RNA expression pattern
PBB GE APOE 203382 s at tn.png
PBB GE APOE 203381 s at.png
PBB GE APOE 212884 x at.png
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 [1] [2]

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[edit]

Gene[edit]

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[edit]

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[edit]

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:

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[edit]

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]

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) [39] to natural killer T cell as well as modulation of inflammation and oxidation.[40] 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.[41]

Clinical Significance[edit]

Alzheimer's disease[edit]

The E4 variant is the largest known genetic risk factor for late-onset sporadic Alzheimer's disease (AD) in a variety of ethnic groups.[42] 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.[43] 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.[44]

The pivotal role of ApoE in AD was first identified through linkage analysis by Margaret Pericak-Vance[45] while working in the Roses lab at Duke University[46] 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.[47] There is also evidence that the ApoE2 allele may serve a protective role in AD.[48] 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.[49]

Estimated worldwide human allele frequencies of ApoE * in Caucasian population[49]
Allele ε2 ε3 ε4
General Frequency 8.4% 77.9% 13.7%
AD Frequency 3.9% 59.4% 36.7%

Atherosclerosis[edit]

Knockout mice that lack the apolipoprotein-E gene (ApoE/) develop extreme hypercholesterolemia when fed a high-fat diet.[50]

Interactions[edit]

Interactive pathway map[edit]

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

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

References[edit]

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Further reading[edit]

External links[edit]