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APOE

The protein encoded by this gene is a major apoprotein of the chylomicron. It binds to a specific liver and peripheral cell receptor, and is essential for the normal catabolism of triglyceride-rich lipoprotein constituents. This gene maps to chromosome 19 in a cluster with the related apolipoprotein C1 and C2 genes. Mutations in this gene result in familial dysbetalipoproteinemia, or type III hyperlipoproteinemia (HLP III), in which increased plasma cholesterol and triglycerides are the consequence of impaired clearance of chylomicron and VLDL remnants. [provided by RefSeq, Jun 2016]
Full Name
Apolipoprotein E
Function
APOE is an apolipoprotein, a protein associating with lipid particles, that mainly functions in lipoprotein-mediated lipid transport between organs via the plasma and interstitial fluids (PubMed:6860692, PubMed:1911868, PubMed:14754908). APOE is a core component of plasma lipoproteins and is involved in their production, conversion and clearance (PubMed:6860692, PubMed:2762297, PubMed:1911868, PubMed:1917954, PubMed:9395455, PubMed:14754908, PubMed:23620513). Apoliproteins are amphipathic molecules that interact both with lipids of the lipoprotein particle core and the aqueous environment of the plasma (PubMed:6860692, PubMed:2762297, PubMed:9395455). As such, APOE associates with chylomicrons, chylomicron remnants, very low density lipoproteins (VLDL) and intermediate density lipoproteins (IDL) but shows a preferential binding to high-density lipoproteins (HDL) (PubMed:6860692, PubMed:1911868). It also binds a wide range of cellular receptors including the LDL receptor/LDLR, the LDL receptor-related proteins LRP1, LRP2 and LRP8 and the very low-density lipoprotein receptor/VLDLR that mediate the cellular uptake of the APOE-containing lipoprotein particles (PubMed:2762297, PubMed:1917954, PubMed:7768901, PubMed:8939961, PubMed:12950167, PubMed:20030366, PubMed:2063194, PubMed:8756331, PubMed:20303980, PubMed:1530612, PubMed:7635945). Finally, APOE has also a heparin-binding activity and binds heparan-sulfate proteoglycans on the surface of cells, a property that supports the capture and the receptor-mediated uptake of APOE-containing lipoproteins by cells (PubMed:9395455, PubMed:9488694, PubMed:23676495, PubMed:7635945). A main function of APOE is to mediate lipoprotein clearance through the uptake of chylomicrons, VLDLs, and HDLs by hepatocytes (PubMed:1911868, PubMed:1917954, PubMed:9395455, PubMed:23676495, PubMed:29516132). APOE is also involved in the biosynthesis by the liver of VLDLs as well as their uptake by peripheral tissues ensuring the delivery of triglycerides and energy storage in muscle, heart and adipose tissues (PubMed:2762297, PubMed:29516132). By participating in the lipoprotein-mediated distribution of lipids among tissues, APOE plays a critical role in plasma and tissues lipid homeostasis (PubMed:2762297, PubMed:1917954, PubMed:29516132). APOE is also involved in two steps of reverse cholesterol transport, the HDLs-mediated transport of cholesterol from peripheral tissues to the liver, and thereby plays an important role in cholesterol homeostasis (PubMed:9395455, PubMed:14754908, PubMed:23620513). First, it is functionally associated with ABCA1 in the biogenesis of HDLs in tissues (PubMed:14754908, PubMed:23620513). Second, it is enriched in circulating HDLs and mediates their uptake by hepatocytes (PubMed:9395455). APOE also plays an important role in lipid transport in the central nervous system, regulating neuron survival and sprouting (PubMed:8939961, PubMed:25173806). APOE in also involved in innate and adaptive immune responses, controlling for instance the survival of myeloid-derived suppressor cells (By similarity). APOE, may also play a role in transcription regulation through a receptor-dependent and cholesterol-independent mechanism, that activates MAP3K12 and a non-canonical MAPK signal transduction pathway that results in enhanced AP-1-mediated transcription of APP (PubMed:28111074).
(Microbial infection) Through its interaction with HCV envelope glycoprotein E2, participates in the attachment of HCV to HSPGs and other receptors (LDLr, VLDLr, and SR-B1) on the cell surface and to the assembly, maturation and infectivity of HCV viral particles (PubMed:25122793, PubMed:29695434). This interaction is probably promoted via the up-regulation of cellular autophagy by the virus (PubMed:29695434).
Biological Process
AMPA glutamate receptor clustering Source: Alzheimers_University_of_Toronto
Amyloid precursor protein metabolic process Source: UniProtKB
Artery morphogenesis Source: Ensembl
Cellular calcium ion homeostasis Source: Ensembl
Cellular protein metabolic process Source: Reactome
cGMP-mediated signaling Source: BHF-UCL
Cholesterol catabolic process Source: GO_Central
Cholesterol efflux Source: UniProtKB
Cholesterol homeostasis Source: BHF-UCL
Cholesterol metabolic process Source: BHF-UCL
Chylomicron assembly Source: Reactome
Chylomicron remnant clearance Source: UniProtKB
Chylomicron remodeling Source: Reactome
Cytoskeleton organization Source: UniProtKB
Fatty acid homeostasis Source: Alzheimers_University_of_Toronto
Gene expression Source: Ensembl
G protein-coupled receptor signaling pathway Source: BHF-UCL
High-density lipoprotein particle assembly Source: UniProtKB
High-density lipoprotein particle clearance Source: BHF-UCL
High-density lipoprotein particle remodeling Source: BHF-UCL
Intermediate-density lipoprotein particle clearance Source: UniProtKB
Intracellular receptor signaling pathway Source: Reactome
Intracellular transport Source: UniProtKB
Lipid transport involved in lipid storage Source: BHF-UCL
Lipoprotein biosynthetic process Source: UniProtKB
Lipoprotein catabolic process Source: GO_Central
Locomotory exploration behavior Source: ARUK-UCL
Long-chain fatty acid transport Source: Alzheimers_University_of_Toronto
Long-term memory Source: ARUK-UCL
Low-density lipoprotein particle remodeling Source: Ensembl
Maintenance of location in cell Source: Ensembl
Negative regulation of amyloid-beta formation Source: Alzheimers_University_of_Toronto
Negative regulation of amyloid fibril formation Source: UniProtKB
Negative regulation of blood coagulation Source: BHF-UCL
Negative regulation of blood vessel endothelial cell migration Source: BHF-UCL
Negative regulation of canonical Wnt signaling pathway Source: ARUK-UCL
Negative regulation of cellular protein metabolic process Source: ARUK-UCL
Negative regulation of cholesterol biosynthetic process Source: BHF-UCL
Negative regulation of cholesterol efflux Source: Alzheimers_University_of_Toronto
Negative regulation of dendritic spine development Source: Alzheimers_University_of_Toronto
Negative regulation of dendritic spine maintenance Source: Alzheimers_University_of_Toronto
Negative regulation of endothelial cell migration Source: ARUK-UCL
Negative regulation of endothelial cell proliferation Source: BHF-UCL
Negative regulation of gene expression Source: ARUK-UCL
Negative regulation of inflammatory response Source: BHF-UCL
Negative regulation of lipid biosynthetic process Source: Alzheimers_University_of_Toronto
Negative regulation of lipid transport across blood-brain barrier Source: Alzheimers_University_of_Toronto
Negative regulation of long-term synaptic potentiation Source: ARUK-UCL
Negative regulation of MAP kinase activity Source: BHF-UCL
Negative regulation of neuron apoptotic process Source: GO_Central
Negative regulation of neuron death Source: Alzheimers_University_of_Toronto
Negative regulation of neuron projection development Source: ARUK-UCL
Negative regulation of phospholipid efflux Source: Alzheimers_University_of_Toronto
Negative regulation of platelet activation Source: BHF-UCL
Negative regulation of postsynaptic membrane organization Source: Alzheimers_University_of_Toronto
Negative regulation of protein secretion Source: UniProtKB
Negative regulation of triglyceride metabolic process Source: Ensembl
Neuron projection development Source: UniProtKB
Nitric oxide mediated signal transduction Source: BHF-UCL
NMDA glutamate receptor clustering Source: Alzheimers_University_of_Toronto
Phospholipid efflux Source: BHF-UCL
Positive regulation by host of viral process Source: AgBase
Positive regulation of amyloid-beta clearance Source: UniProtKB
Positive regulation of amyloid-beta formation Source: Alzheimers_University_of_Toronto
Positive regulation of amyloid fibril formation Source: ARUK-UCL
Positive regulation of cholesterol efflux Source: Alzheimers_University_of_Toronto
Positive regulation of cholesterol esterification Source: BHF-UCL
Positive regulation of dendritic spine development Source: Alzheimers_University_of_Toronto
Positive regulation of dendritic spine maintenance Source: Alzheimers_University_of_Toronto
Positive regulation of endocytosis Source: ARUK-UCL
Positive regulation of ERK1 and ERK2 cascade Source: UniProtKB
Positive regulation of heparan sulfate binding Source: ARUK-UCL
Positive regulation of heparan sulfate proteoglycan binding Source: ARUK-UCL
Positive regulation of lipid biosynthetic process Source: Alzheimers_University_of_Toronto
Positive regulation of lipid transport across blood-brain barrier Source: Alzheimers_University_of_Toronto
Positive regulation of low-density lipoprotein particle receptor catabolic process Source: BHF-UCL
Positive regulation of membrane protein ectodomain proteolysis Source: BHF-UCL
Positive regulation of neurofibrillary tangle assembly Source: Alzheimers_University_of_Toronto
Positive regulation of neuron death Source: Alzheimers_University_of_Toronto
Positive regulation of neuron projection development Source: ARUK-UCL
Positive regulation of nitric-oxide synthase activity Source: BHF-UCL
Positive regulation of phospholipid efflux Source: Alzheimers_University_of_Toronto
Positive regulation of presynaptic membrane organization Source: ARUK-UCL
Positive regulation of transcription, DNA-templated Source: UniProtKB
Post-translational protein modification Source: Reactome
Protein import Source: Alzheimers_University_of_Toronto
Receptor-mediated endocytosis Source: BHF-UCL
Regulation of amyloid-beta clearance Source: Alzheimers_University_of_Toronto
Regulation of amyloid fibril formation Source: ARUK-UCL
Regulation of amyloid precursor protein catabolic process Source: UniProtKB
Regulation of axon extension Source: UniProtKB
Regulation of behavioral fear response Source: ARUK-UCL
Regulation of Cdc42 protein signal transduction Source: BHF-UCL
Regulation of cellular response to very-low-density lipoprotein particle stimulus Source: ARUK-UCL
Regulation of cholesterol metabolic process Source: ARUK-UCL
Regulation of innate immune response Source: Ensembl
Regulation of neuronal synaptic plasticity Source: UniProtKB
Regulation of neuron death Source: Alzheimers_University_of_Toronto
Regulation of proteasomal protein catabolic process Source: UniProtKB
Regulation of protein-containing complex assembly Source: ARUK-UCL
Regulation of protein metabolic process Source: ARUK-UCL
Regulation of tau-protein kinase activity Source: Alzheimers_University_of_Toronto
Regulation of transcription by RNA polymerase II Source: Reactome
Response to caloric restriction Source: ARUK-UCL
Response to dietary excess Source: Ensembl
Response to reactive oxygen species Source: UniProtKB
Retinoid metabolic process Source: Reactome
Reverse cholesterol transport Source: BHF-UCL
Synaptic transmission, cholinergic Source: UniProtKB
Triglyceride homeostasis Source: BHF-UCL
Triglyceride metabolic process Source: BHF-UCL
Triglyceride-rich lipoprotein particle clearance Source: UniProtKB
Vasodilation Source: Ensembl
Very-low-density lipoprotein particle clearance Source: UniProtKB
Very-low-density lipoprotein particle remodeling Source: BHF-UCL
Virion assembly Source: AgBase
Cellular Location
Secreted; Extracellular space; extracellular matrix. In the plasma, APOE is associated with chylomicrons, chylomicrons remnants, VLDL, LDL and HDL lipoproteins (PubMed:1911868, PubMed:8340399). Lipid poor oligomeric APOE is associated with the extracellular matrix in a calcium- and heparan-sulfate proteoglycans-dependent manner (PubMed:9488694). Lipidation induces the release from the extracellular matrix (PubMed:9488694).
Involvement in disease
Hyperlipoproteinemia 3 (HLPP3): The disease is caused by variants affecting the gene represented in this entry. The vast majority of the patients are homozygous for APOE*2 alleles. More severe cases of HLPP3 have also been observed in individuals heterozygous for rare APOE variants. The influence of APOE on lipid levels is often suggested to have major implications for the risk of coronary artery disease (CAD). Individuals carrying the common APOE*4 variant are at higher risk of CAD. A disorder characterized by the accumulation of intermediate-density lipoprotein particles (IDL or broad-beta-lipoprotein) rich in cholesterol. Clinical features include xanthomas, yellowish lipid deposits in the palmar crease, or less specific on tendons and on elbows. The disorder rarely manifests before the third decade in men. In women, it is usually expressed only after the menopause.
Alzheimer disease 2 (AD2): Disease susceptibility is associated with variants affecting the gene represented in this entry. The APOE*4 allele (APOE form E4) is genetically associated with the common late onset familial and sporadic forms of Alzheimer disease. Risk for AD increased from 20% to 90% and mean age at onset decreased from 84 to 68 years with increasing number of APOE*4 alleles in 42 families with late onset AD. Thus APOE*4 gene dose is a major risk factor for late onset AD and, in these families, homozygosity for APOE*4 was virtually sufficient to cause AD by age 80. The mechanism by which APOE*4 participates in pathogenesis is not known. A late-onset form of Alzheimer disease. Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituents of these plaques are neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, that are produced by the proteolysis of the transmembrane APP protein. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products, such as C31, are also implicated in neuronal death.
Sea-blue histiocyte disease (SBHD): Characterized by splenomegaly, mild thrombocytopenia and, in the bone marrow, numerous histiocytes containing cytoplasmic granules which stain bright blue with the usual hematologic stains. The syndrome is the consequence of an inherited metabolic defect analogous to Gaucher disease and other sphingolipidoses.
Lipoprotein glomerulopathy (LPG): Uncommon kidney disease characterized by proteinuria, progressive kidney failure, and distinctive lipoprotein thrombi in glomerular capillaries.
PTM
APOE exists as multiple glycosylated and sialylated glycoforms within cells and in plasma (PubMed:29516132). The extent of glycosylation and sialylation are tissue and context specific (PubMed:29516132). Plasma APOE undergoes desialylation and is less glycosylated and sialylated than the cellular form (PubMed:2498325, PubMed:19838169, PubMed:20511397, PubMed:23234360). Glycosylation is not required for proper expression and secretion (PubMed:2498325). O-glycosylated with core 1 or possibly core 8 glycans. Thr-307 and Ser-314 are minor glycosylation sites compared to Ser-308 (PubMed:19838169, PubMed:23234360).
Glycated in plasma VLDL of normal subjects, and of hyperglycemic diabetic patients at a higher level (2-3 fold).
Phosphorylated by FAM20C in the extracellular medium.
Undergoes C-terminal proteolytic processing in neurons. C-terminally truncated APOE has a tendency to form neurotoxic intracellular neurofibrillary tangle-like inclusions in neurons.

Anti-APOE antibodies

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Target: APOE
Host: Mouse
Antibody Isotype: IgG1, κ
Specificity: Mouse, Human, Zebrafish
Clone: A1
Application*: P, WB, IF, IP
Target: APOE
Host: Mouse
Antibody Isotype: IgG1
Specificity: Human
Clone: 0076
Application*: WB, IF
Target: APOE
Host: Rabbit
Antibody Isotype: IgG
Specificity: Human, Mouse, Rat
Clone: BA0020
Application*: IF, IH, P, WB
Target: APOE
Host: Mouse
Antibody Isotype: IgG1, κ
Specificity: Human
Clone: IB5-E1
Application*: WB
Target: APOE
Host: Mouse
Antibody Isotype: IgG1, κ
Specificity: Human
Clone: E8
Application*: WB, IF, IP, E
Target: APOE
Host: Mouse
Antibody Isotype: IgG1
Specificity: Human
Clone: 1F9
Application*: IH, IP, WB
Target: APOE
Host: Mouse
Antibody Isotype: IgG1, κ
Specificity: Human, Mouse, Rat
Clone: WU E-4
Application*: P, WB, IF, IP
Target: APOE
Host: Mouse
Antibody Isotype: IgG2a, κ
Specificity: Human
Clone: 13B40
Application*: P, WB, IF, IP, E
Target: APOE
Host: Mouse
Antibody Isotype: IgG2a, κ
Specificity: Human, Mouse, Rat
Clone: CBLNA-173
Application*: P, WB, IF, IP, E
More Infomation
For Research Use Only. Not For Clinical Use.
(P): Predicted
* Abbreviations
IFImmunofluorescence
IHImmunohistochemistry
IPImmunoprecipitation
WBWestern Blot
EELISA
MMicroarray
CIChromatin Immunoprecipitation
FFlow Cytometry
FNFunction Assay
IDImmunodiffusion
RRadioimmunoassay
TCTissue Culture
GSGel Supershift
NNeutralization
BBlocking
AActivation
IInhibition
DDepletion
ESELISpot
DBDot Blot
MCMass Cytometry/CyTOF
CTCytotoxicity
SStimulation
AGAgonist
APApoptosis
IMImmunomicroscopy
BABioassay
CSCostimulation
EMElectron Microscopy
IEImmunoelectrophoresis
PAPeptide Array
ICImmunocytochemistry
PEPeptide ELISA
MDMeDIP
SHIn situ hybridization
IAEnzyme Immunoassay
SEsandwich ELISA
PLProximity Ligation Assay
ECELISA(Cap)
EDELISA(Det)
BIBioimaging
IOImmunoassay
LFLateral Flow Immunoassay
LALuminex Assay
CImmunohistochemistry-Frozen Sections
PImmunohistologyp-Paraffin Sections
ISIntracellular Staining for Flow Cytometry
MSElectrophoretic Mobility Shift Assay
RIRNA Binding Protein Immunoprecipitation (RIP)
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