Apolipoprotein AI

APOA1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1AV1, 1GW3, 1GW4, 1ODP, 1ODQ, 1ODR, 2A01, 3K2S, 3R2P, 2MSC, 2MSD, 2MSE, 4V6M
Identifiers
Aliases	APOA1, entrez:335, apo(a), apolipoprotein A1, Apolipoprotein A-I, HPALP2
External IDs	OMIM: 107680; MGI: 88049; HomoloGene: 47900; GeneCards: APOA1; OMA:APOA1 - orthologs
Gene location (Human) Chr. Chromosome 11 (human)[1] Band 11q23.3 Start 116,835,751 bp[1] End 116,837,622 bp[1]
Gene location (Mouse) Chr. Chromosome 9 (mouse)[2] Band 9 A5.2|9 25.36 cM Start 46,139,878 bp[2] End 46,141,764 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in jejunal mucosa right lobe of liver mucosa of ileum right testis left testis duodenum apex of heart gonad left ventricle amniotic fluid Top expressed in left lobe of liver jejunum yolk sac duodenum epithelium of stomach gallbladder ileum fetal liver hematopoietic progenitor cell migratory enteric neural crest cell mucous cell of stomach More reference expression data BioGPS More reference expression data
Gene ontology Molecular function lipase inhibitor activity phosphatidylcholine binding apolipoprotein receptor binding high-density lipoprotein particle receptor binding lipoprotein particle binding phosphatidylcholine-sterol O-acyltransferase activator activity phospholipid binding apolipoprotein A-I receptor binding enzyme binding cholesterol transfer activity amyloid-beta binding phospholipid transporter activity protein binding chemorepellent activity lipid transporter activity cholesterol binding identical protein binding high-density lipoprotein particle binding lipid binding heat shock protein binding signaling receptor binding Cellular component cytosol endoplasmic reticulum lumen chylomicron extracellular region nucleus extracellular vesicle endocytic vesicle lumen discoidal high-density lipoprotein particle very-low-density lipoprotein particle cell surface secretory granule lumen extracellular exosome blood microparticle endocytic vesicle plasma membrane spherical high-density lipoprotein particle early endosome high-density lipoprotein particle cytoplasmic vesicle extracellular space low-density lipoprotein particle intermediate-density lipoprotein particle collagen-containing extracellular matrix Biological process positive regulation of Rho protein signal transduction regulation of protein phosphorylation cholesterol import lipid transport negative chemotaxis positive regulation of cholesterol esterification phospholipid efflux phospholipid transport negative regulation of hydrolase activity receptor-mediated endocytosis retinoid metabolic process negative regulation of lipase activity regulation of intestinal cholesterol absorption negative regulation of cell adhesion molecule production peripheral nervous system axon regeneration endothelial cell proliferation animal organ regeneration peptidyl-methionine modification cholesterol homeostasis negative regulation of heterotypic cell-cell adhesion transforming growth factor beta receptor signaling pathway negative regulation of inflammatory response phospholipid homeostasis ERK1 and ERK2 cascade negative regulation of cytokine production involved in immune response positive regulation of fatty acid biosynthetic process high-density lipoprotein particle clearance lipoprotein metabolic process G protein-coupled receptor signaling pathway positive regulation of triglyceride catabolic process response to nutrient glucocorticoid metabolic process lipid storage protein stabilization positive regulation of lipoprotein lipase activity cholesterol metabolic process response to estrogen triglyceride catabolic process transmembrane transport transport cholesterol efflux integrin-mediated signaling pathway phosphatidylcholine biosynthetic process neuron projection regeneration negative regulation of very-low-density lipoprotein particle remodeling steroid metabolic process positive regulation of hydrolase activity regulation of Cdc42 protein signal transduction blood vessel endothelial cell migration negative regulation of tumor necrosis factor-mediated signaling pathway lipid metabolism cholesterol transport platelet degranulation adrenal gland development high-density lipoprotein particle assembly negative regulation of response to cytokine stimulus high-density lipoprotein particle remodeling positive regulation of substrate adhesion-dependent cell spreading phospholipid metabolic process vitamin transport cholesterol biosynthetic process positive regulation of stress fiber assembly triglyceride homeostasis reverse cholesterol transport lipoprotein biosynthetic process positive regulation of cholesterol efflux regulation of lipid metabolic process regulation of cholesterol transport chylomicron remodeling very-low-density lipoprotein particle remodeling chylomicron assembly post-translational protein modification positive regulation of lipid biosynthetic process positive regulation of phagocytosis positive regulation of phospholipid efflux Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 335 11806 Ensembl ENSG00000118137 ENSMUSG00000032083 UniProt P02647 Q00623 RefSeq (mRNA) NM_000039 NM_001318017 NM_001318018 NM_001318021 NM_009692 RefSeq (protein) NP_000030 NP_001304946 NP_001304947 NP_001304950 NP_000030.1 NP_001304946.1 NP_001304947.1 NP_033822 Location (UCSC) Chr 11: 116.84 – 116.84 Mb Chr 9: 46.14 – 46.14 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Apolipoprotein AI (Apo-AI) is a protein that in humans is encoded by the APOA1 gene.^[5][6] As the major component of HDL particles, it has a specific role in lipid metabolism.

APOA1 is located on chromosome 11, with its specific location being 11q23-q24. The gene contains 4 exons.^[7] The encoded apolipoprotein AI, is a 28.1 kDa protein composed of 243 amino acids; 21 peptides have been observed through mass spectrometry data.^[8][9] Due to alternative splicing, there exists multiple transcript variants of APOA1, including at least one which encodes a Apo-AI preprotein.^[7]

Apolipoprotein AI is the major protein component of high density lipoprotein (HDL) particles in plasma.^[10]

Chylomicrons secreted from the intestinal enterocyte also contain Apo-AI, but it is quickly transferred to HDL in the bloodstream.^[11]

The protein, as a component of HDL particles, enables efflux of fat molecules by accepting fats from within cells (including macrophages within the walls of arteries which have become overloaded with ingested fats from oxidized LDL particles) for transport (in the water outside cells) elsewhere, including back to LDL particles or to the liver for excretion.

It is a cofactor for lecithin–cholesterol acyltransferase (LCAT) which is responsible for the formation of most plasma cholesteryl esters. Apolipoprotein AI has also been isolated as a prostacyclin (PGI2) stabilizing factor, and thus may have an anticlotting effect.^[12] Defects in the gene encoding it are associated with HDL deficiencies, including Tangier disease, and with systemic non-neuropathic amyloidosis.^[7]

Apo-AI is often used as a biomarker for prediction of cardiovascular diseases. The ratio apoB-100/apoA-I (i.e. LDL & larger particles vs. HDL particles), NMR measured lipoprotein (low density lipoprotein (LDL)/(HDL) particle ratios even more so, has always had a stronger correlation with myocardial infarction event rates than older methods of measuring lipid transport in the water outside cells.^[13]

Apo-AI is routinely measured using immunoassays such as ELISA or nephelometry.

Apo-AI can be used to create in vitro lipoprotein nanodiscs for cell-free membrane expression systems.^[14]

As a major component of the high-density lipoprotein complex (protective "fat removal" particles), Apo-AI helps to clear fats, including cholesterol, from white blood cells within artery walls, making the white blood cells (WBCs) less likely to become fat overloaded, transform into foam cells, die and contribute to progressive atheroma. Five of nine men found to carry a mutation (E164X) who were at least 35 years of age had developed premature coronary artery disease.^[15] One of four mutants of Apo-AI is present in roughly 0.3% of the Japanese population, but is found in 6% of those with low HDL cholesterol levels.^[16]

ApoA-I Milano is a naturally occurring mutant of Apo-AI, found in a few families in Limone sul Garda, Italy, and, by genetic + church record family tree detective work, traced to a single individual, Giovanni Pomarelli, in the 18th century.^[17] Described in 1980, it was the first known molecular abnormality of apolipoproteins.^[18] Paradoxically, carriers of this mutation have very low HDL-C (HDL-Cholesterol) levels, but no increase in the risk of heart disease, often living to age 100 or older. This unusual observation was what lead Italian investigators to track down what was going on and lead to the discovery of apoA-I Milano (the city, Milano, ~160 km away, in which the researcher's lab was located). Biochemically, apo A1 contains an extra cysteine bridge, causing it to exist as a homodimer or as a heterodimer with Apo-AII. However, the enhanced cardioprotective activity of this mutant (which likely depends on fat & cholesterol efflux) cannot easily be replicated by other cysteine mutants.^[19]

Recombinant Apo-AI Milano dimers formulated into liposomes can reduce atheromas in animal models by up to 30%.^[20] Apo-AI Milano has also been shown in small clinical trials to have a statistically significant effect in reducing (reversing) plaque build-up on arterial walls.^[21][22]

In human trials the reversal of plaque build-up was measured over the course of five weeks.^[21][23]

A study from 2008 describes two novel susceptibility haplotypes, P2-S2-X1 and P1-S2-X1, discovered in ApoAI-CIII-AIV gene cluster on chromosome 11q23, which confer approximately threefold higher risk of coronary heart disease in normal^[24] as well as in the patients having type 2 diabetes mellitus.^[25]

A G/A polymorphism in the promoter of the APOA1 gene has been associated with the age at which Alzheimer disease is presented.^[26] Protection from Alzheimer's disease by Apo-AI may rely on a synergistic interaction with alpha-tocopherol.^[27] Amyloid deposited in the knee following surgery consists largely of Apo-AI secreted from chondrocytes (cartilage cells).^[28] A wide variety of amyloidosis symptoms are associated with rare APOA1 mutants.

Apo-AI binds to lipopolysaccharide or endotoxin, and has a major role in the anti-endotoxin function of HDL.^[29]

In one study, a decrease in Apo-AI levels was detected in schizophrenia patients' CSF, brain and peripheral tissues.^[30]

Apolipoprotein AI and ApoE interact epistatically to modulate triglyceride levels in coronary heart disease patients. Individually, neither Apo-AI nor ApoE was found to be associated with triglyceride (TG) levels, but pairwise epistasis (additive x additive model) explored their significant synergistic contributions with raised TG levels (P<0.01). ^[31]

In a study from 2005 it was reported, that Apo-AI production is decreased by calcitriol. It was concluded, that this regulation happens on transcription level: calcitriol alters yet unknown coactivators or corepressors, resulting in repression of APOA1 promoter activity. Simultaneously, Apo-AI production was increased by vitamin D antagonist, ZK-191784.^[32]

Exercise or statin treatment may cause an increase in HDL-C levels by inducing Apo-AI production, but this depends on the G/A promoter polymorphism.^[33]

Apolipoprotein A1 has been shown to interact with:

• ABCA1^[34]
• GPLD1^[35]
• PLTP^[36]

Apolipoprotein AI binding precursor, a relative of APOA-1 abbreviated APOA1BP, has a predicted biochemical interaction with carbohydrate kinase domain containing protein. The relationship between these two proteins is substantiated by cooccurance across genomes and coexpression.^[37] The ortholog of CARKD in E. coli contains a domain not present in any eukaryotic ortholog. This domain has a high sequence identity to APOA1BP. CARKD is a protein of unknown function, and the biochemical basis for this interaction is unknown.

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

[[File:

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

|alt=Statin pathway edit]]

Statin pathway edit

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

• Apolipoprotein B
• Cardiovascular disease
• ApoA-1 Milano

• Apolipoprotein+A-I at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Applied Research on Apolipoprotein-A1
• Human APOA1 genome location and APOA1 gene details page in the UCSC Genome Browser.
• Overview of all the structural information available in the PDB for UniProt: P02647 (Human Apolipoprotein A-I) at the PDBe-KB.
• Overview of all the structural information available in the PDB for UniProt: Q00623 (Mouse Apolipoprotein A-I) at the PDBe-KB.