Apolipoprotein A1

Apolipoprotein A-I

PDB rendering based on 1av1.

Available structures
PDB	1AV1, 1GW3, 1GW4, 1ODP, 1ODQ, 1ODR, 2A01, 3K2S

Identifiers

Symbols

APOA1; MGC117399

External IDs

OMIM: 107680 MGI: 88049 HomoloGene: 47900 GeneCards: APOA1 Gene

Gene Ontology
Molecular function	• beta-amyloid binding • lipid transporter activity • protein binding • phospholipid binding • high-density lipoprotein particle binding • cholesterol binding • cholesterol transporter activity • cholesterol transporter activity • enzyme binding • apolipoprotein receptor binding • apolipoprotein A-I receptor binding • identical protein binding • phosphatidylcholine-sterol O-acyltransferase activator activity • high-density lipoprotein particle receptor binding
Cellular component	• extracellular region • extracellular region • extracellular space • endoplasmic reticulum lumen • endoplasmic reticulum lumen • plasma membrane • plasma membrane • endocytic vesicle • stored secretory granule • cytoplasmic vesicle • very-low-density lipoprotein particle • high-density lipoprotein particle • spherical high-density lipoprotein particle
Biological process	• regulation of protein phosphorylation • endothelial cell proliferation • platelet degranulation • negative regulation of cytokine secretion involved in immune response • lipid metabolic process • phospholipid metabolic process • phosphatidylcholine biosynthetic process • cholesterol biosynthetic process • G-protein coupled receptor protein signaling pathway • blood coagulation • steroid metabolic process • cholesterol metabolic process • glucocorticoid metabolic process • positive regulation of cholesterol esterification • negative regulation of very-low-density lipoprotein particle remodeling • lipid storage • platelet activation • regulation of intestinal cholesterol absorption • cholesterol transport • adrenal gland development • Cdc42 protein signal transduction • cholesterol efflux • phospholipid efflux • high-density lipoprotein particle remodeling • high-density lipoprotein particle assembly • high-density lipoprotein particle clearance • lipoprotein metabolic process • lipoprotein biosynthetic process • cholesterol homeostasis • blood vessel endothelial cell migration • reverse cholesterol transport • cellular lipid metabolic process • negative regulation of interleukin-1 beta secretion • protein stabilization • positive regulation of hydrolase activity • negative regulation of hydrolase activity • positive regulation of transferase activity • transmembrane transport • cholesterol import
Sources: Amigo / QuickGO

RNA expression pattern

More reference expression data

Orthologs

Species

Human

Mouse

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr 11:
116.71 – 116.71 Mb

Chr 9:
46.04 – 46.04 Mb

PubMed search

[1]

[2]

Apolipoprotein A-I is a protein that in humans is encoded by the APOA1 gene.^[1]^[2] It has a specific role in lipid metabolism.

Apolipoprotein A-I is the major protein component of high density lipoprotein (HDL) in plasma. Chylomicrons secreted from the intestinal enterocyte also contain ApoA1 but it is quickly transferred to HDL in the bloodstream ^[3]. The protein promotes cholesterol efflux from tissues to the liver for excretion. It is a cofactor for [Lecithin-cholesterol acyltransferase|lecithin cholesterolacyltransferase]] (LCAT) which is responsible for the formation of most plasma cholesteryl esters. ApoA-I was also isolated as a prostacyclin (PGI2) stabilizing factor, and thus may have an anticlotting effect.^[4] Defects in the gene encoding it are associated with HDL deficiencies, including Tangier disease, and with systemic non-neuropathic amyloidosis.^[5]

It has an approximate molecular weight 28 KDa^[6].

1 Activity associated with high HDL-C and protection from heart disease
2 Novel Haplotypes within Apolipoprotein AI-CIII-AIV gene cluster
3 Role in other diseases
4 Epistatic impact of ApoA-I
5 Factors affecting ApoA-I activity
6 Potential Binding Partners
7 Interactions
8 Interactive pathway map
9 See also
10 References
11 External links

Activity associated with high HDL-C and protection from heart disease

As a major component of the high-density lipoprotein complex ("good cholesterol"), ApoA-I helps to clear cholesterol from arteries. Five of nine men found to carry a mutation (E164X) who were at least 35 years of age had developed premature coronary artery disease.^[7] One of four mutants of ApoA-I is present in roughly 0.3% of the Japanese population, but is found 6% of those with low HDL cholesterol levels.

ApoA-1 Milano is a naturally occurring mutant of ApoA-I, found in a family descended from a single couple of the 18th century. Described in 1980, it was the first known molecular abnormality of apolipoproteins.^[8] Paradoxically, carriers of this mutation have very low HDL cholesterol levels, but no increase in the risk of heart disease. Biochemically, ApoA-I contains an extra cysteine bridge, causing it to exist as a homodimer or as a heterodimer with ApoA-II. However, the enhanced cardioprotective activity of this mutant (which likely depends on cholesterol efflux) cannot easily be replicated by other cysteine mutants.^[9]

Recombinant Apo-I Milano dimers formulated into liposomes can reduce atheromas in animal models by up to 30%.^[10] ApoA-I Milano has also been shown in small clinical trials to have a statistically significant effect in reducing (reversing) plaque build-up on arterial walls.^[11]^[12]

In human trials the reversal of plaque build-up was measured over the course of five weeks.^[11]^[13]

Novel Haplotypes within Apolipoprotein AI-CIII-AIV gene cluster

Lately, two novel susceptibility haplotypes i.e. P2-S2-X1 and P1-S2-X1 have been discovered in ApoAI-CIII-AIV gene cluster on chromosme 11q23, which confer approximately threefold higher risk of coronary heart disease in normal^[14] as well as in the patients having non-insulin diabetes mellitus.^[15]

Role in other diseases

A G/A polymorphism in the promoter of the ApoA-I gene has been associated with the age at which patients presented with Alzheimer disease.^[16] Protection from Alzheimer disease by ApoA1 may rely on a synergistic interaction with alpha-tocopherol.^[17] Amyloid deposited in the knee following surgery consists largely of ApoA-I secreted from chondrocytes (cartilage cells).^[18] A wide variety of amyloidosis symptoms are associated with rare ApoA-I mutants.

ApoA-I binds to lipopolysaccharide or endotoxin, and has a major role in the anti-endotoxin function of HDL.^[19]

In one study, a decrease in ApoA1 levels was detected in schizophrenia patients' CSF, brain and peripheral tissues.^[20]

Epistatic impact of ApoA-I

Apolipoprotein A-I and APOE interact epistatically to modulate triglyceride levels in Coronary Heart Disease patients.Individually, neither ApoA-I nor ApoE was found to be associated with TG levels however, pairwise epistasis (additive x additive model) explored their significant synergistic contributions with raised TG levels (P<0.01). ^[21]

Factors affecting ApoA-I activity

ApoA-I production is decreased by calcitriol, and increased by a drug that antagonizes it.^[22]

Exercise or statin treatment may cause an increase in HDL-C levels by inducing ApoA-I production, but this depends on the G/A promoter polymorphism.^[23]

Potential Binding Partners

Apolipoprotein A-1 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, Coexpression, and Rosetta Stone Analysis.^[24] 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.

Interactions

Apolipoprotein A1 has been shown to interact with ABCA1,^[25] GPLD1^[26] and PLTP.^[27]

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles. ^[28]

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Statin Pathway edit

References

^ Breslow JL, Ross D, McPherson J, Williams H, Kurnit D, Nussbaum AL, Karathanasis SK, Zannis VI (November 1982). "Isolation and characterization of cDNA clones for human apolipoprotein A-I". Proc. Natl. Acad. Sci. U.S.A. 79 (22): 6861–5. doi:10.1073/pnas.79.22.6861. PMC 347233. PMID 6294659. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=347233.
^ Arinami T, Hirano T, Kobayashi K, Yamanouchi Y, Hamaguchi H (June 1990). "Assignment of the apolipoprotein A-I gene to 11q23 based on RFLP in a case with a partial deletion of chromosome 11, del(11)(q23.3----qter)". Hum. Genet. 85 (1): 39–40. PMID 1972696.
^ Wasan KM, Brocks DR, Lee SD, Sachs-Barrable K, Thornton SJ (january 2008). "Impact of lipoproteins on the biological activity and disposition of hydrophobic drugs: implications for drug discovery". Nature Reviews Drug Discovery 7 (1): 84–99. doi:10.1038/nrd2353. PMID 18079757.
^ Yui Y, Aoyama T, Morishita H, Takahashi M, Takatsu Y, Kawai C (1988). "Serum prostacyclin stabilizing factor is identical to apolipoprotein A-I (Apo A-I). A novel function of Apo A-I". J. Clin. Invest. 82 (3): 803–7. doi:10.1172/JCI113682. PMC 303586. PMID 3047170. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=303586.
^ "Entrez Gene: APOA1 apolipoprotein A-I". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=335.
^ http://emedicine.medscape.com/article/121187-overview
^ Dastani Z, Dangoisse C, Boucher B, Desbiens K, Krimbou L, Dufour R, Hegele RA, Pajukanta P, Engert JC, Genest J, Marcil M (March 2006). "A novel nonsense apolipoprotein A-I mutation (apoA-I(E136X)) causes low HDL cholesterol in French Canadians". Atherosclerosis 185 (1): 127–36. doi:10.1016/j.atherosclerosis.2005.05.028. PMID 16023124.
^ Franceschini G, Sirtori M, Gianfranceschi G, Sirtori CR (May 1981). "Relation between the HDL apoproteins and AI isoproteins in subjects with the AIMilano abnormality". Metab. Clin. Exp. 30 (5): 502–9. doi:10.1016/0026-0495(81)90188-8. PMID 6785551.
^ Zhu X, Wu G, Zeng W, Xue H, Chen B (2005). "Cysteine mutants of human apolipoprotein A-I: a study of secondary structural and functional properties". J. Lipid Res. 46 (6): 1303–11. doi:10.1194/jlr.M400401-JLR200. PMID 15805548.
^ Chiesa G, Sirtori CR (2003). "Apolipoprotein A-I(Milano): current perspectives". Curr. Opin. Lipidol. 14 (2): 159–63. doi:10.1097/00041433-200304000-00007. PMID 12642784.
^ ^a ^b "Apo A1-Milano Trial: Where are we now?". Cleveland Clinic. http://www.clevelandclinic.org/heartcenter/pub/news/hot/hdlapoa1.asp?firstCat=1&secondCat=429&thirdCat=602. Retrieved 2008-07-26.
^ Nissen SE, Tsunoda T, Tuzcu EM, Schoenhagen P, Cooper CJ, Yasin M, Eaton GM, Lauer MA, Sheldon WS, Grines CL, Halpern S, Crowe T, Blankenship JC, Kerensky R (November 2003). "Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial". JAMA 290 (17): 2292–300. doi:10.1001/jama.290.17.2292. PMID 14600188.
^ "Apo A-1 Milano". Cedars-Sinai Heart Institute. http://www.cedars-sinai.edu/pf_6189.html. Retrieved 2008-07-26.
^ Singh P, Singh M, Kaur TP, Grewal SS (September 2007). "A novel haplotype in ApoAI-CIII-AIV gene region is detrimental to Northwest Indians with coronary heart disease". Int. J. Cardiol. 130 (3): e93. doi:10.1016/j.ijcard.2007.07.029. PMID 17825930.
^ Singh P, Singh M, Gaur S, Kaur T (June 2007). "The ApoAI-CIII-AIV gene cluster and its relation to lipid levels in type 2 diabetes mellitus and coronary heart disease: determination of a novel susceptible haplotype". Diab Vasc Dis Res 4 (2): 124–9. doi:10.3132/dvdr.2007.030. PMID 17654446.
^ Vollbach H, Heun R, Morris CM, Edwardson JA, McKeith IG, Jessen F, Schulz A, Maier W, Kölsch H (2005). "APOA1 polymorphism influences risk for early-onset nonfamiliar AD". Ann. Neurol. 58 (3): 436–41. doi:10.1002/ana.20593. PMID 16130094.
^ Maezawa I, Jin LW, Woltjer RL, Maeda N, Martin GM, Montine TJ, Montine KS (2004). "Apolipoprotein E isoforms and apolipoprotein AI protect from amyloid precursor protein carboxy terminal fragment-associated cytotoxicity". J. Neurochem. 91 (6): 1312–21. doi:10.1111/j.1471-4159.2004.02818.x. PMID 15584908.
^ Solomon A, Murphy CL, Kestler D, Coriu D, Weiss DT, Makovitzky J, Westermark P (2006). "Amyloid contained in the knee joint meniscus is formed from apolipoprotein A-I". Arthritis Rheum. 54 (11): 3545–50. doi:10.1002/art.22201. PMID 17075859.
^ Ma J, Liao XL, Lou B, Wu MP (2004). "Role of apolipoprotein A-I in protecting against endotoxin toxicity". Acta Biochim. Biophys. Sin. (Shanghai) 36 (6): 419–24. doi:10.1093/abbs/36.6.419. PMID 15188057.
^ Huang JT, Wang L, Prabakaran S, Wengenroth M, Lockstone HE, Koethe D, Gerth CW, Gross S, Schreiber D, Lilley K, Wayland M, Oxley D, Leweke FM, Bahn S (2007). "Independent protein-profiling studies show a decrease in apolipoprotein A1 levels in schizophrenia CSF, brain and peripheral tissues". Mol Psychiatry 13 (12): 1118. doi:10.1038/sj.mp.4002108. PMID 17938634.
^ SinghP, SinghM, Kaur T (2008). "Role of apolipoproteins E and A-I: Epistatic villains of triglyceride mediation in coronary heart disease.". Int J Cardiol 134 (3): 410–2. doi:10.1016/j.ijcard.2007.12.102. PMID 18378026.
^ Wehmeier K, Beers A, Haas MJ, Wong NC, Steinmeyer A, Zugel U, Mooradian AD (2005). "Inhibition of apolipoprotein AI gene expression by 1, 25-dihydroxyvitamin D3". Biochim. Biophys. Acta 1737 (1): 16–26. doi:10.1016/j.bbalip.2005.09.004. PMID 16236546.
^ Lahoz C, Peña R, Mostaza JM, Jiménez J, Subirats E, Pintó X, Taboada M, López-Pastor A (2003). "Apo A-I promoter polymorphism influences basal HDL-cholesterol and its response to pravastatin therapy". Atherosclerosis 168 (2): 289–95. doi:10.1016/S0021-9150(03)00094-7. PMID 12801612.
^ "STRING: Known and Predicted Protein-Protein Interactions". http://string.embl.de/newstring_cgi/show_edge_data.pl?taskId=gboDpgqu9YY_&node1=418518&node2=410384.
^ Fitzgerald, Michael L; Morris Andrea L, Rhee Jeongmi S, Andersson Lorna P, Mendez Armando J, Freeman Mason W (Sep. 2002). "Naturally occurring mutations in the largest extracellular loops of ABCA1 can disrupt its direct interaction with apolipoprotein A-I". J. Biol. Chem. (United States) 277 (36): 33178–87. doi:10.1074/jbc.M204996200. ISSN 0021-9258. PMID 12084722.
^ Deeg, M A; Bierman E L, Cheung M C (Mar. 2001). "GPI-specific phospholipase D associates with an apoA-I- and apoA-IV-containing complex". J. Lipid Res. (United States) 42 (3): 442–51. ISSN 0022-2275. PMID 11254757.
^ Pussinen, P J; Jauhiainen M, Metso J, Pyle L E, Marcel Y L, Fidge N H, Ehnholm C (Jan. 1998). "Binding of phospholipid transfer protein (PLTP) to apolipoproteins A-I and A-II: location of a PLTP binding domain in the amino terminal region of apoA-I". J. Lipid Res. (UNITED STATES) 39 (1): 152–61. ISSN 0022-2275. PMID 9469594.
^ The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430". http://www.wikipathways.org/index.php/Pathway:WP430.