PDB rendering based on 1av1.
|External IDs||ChEMBL: GeneCards:|
|RNA expression pattern|
Apolipoprotein A-I is a protein that in humans is encoded by the APOA1 gene. It has a specific role in lipid metabolism. Recent report suggest that APOA1 mRNA is regulated by endogenously expressed antisense RNA.
Apolipoprotein A-I is the major protein component of high density lipoprotein (HDL) in plasma. Chylomicrons secreted from the intestinal enterocyte also contain apo A-I, but it is quickly transferred to HDL in the bloodstream. The protein promotes fat efflux, including cholesterol, from tissues to the liver for excretion. It is a cofactor for lecithin cholesterolacyltransferase (LCAT) which is responsible for the formation of most plasma cholesteryl esters. Apo A-I was also isolated as a prostacyclin (PGI2) stabilizing factor, and thus may have an anticlotting effect. Defects in the gene encoding it are associated with HDL deficiencies, including Tangier disease, and with systemic non-neuropathic amyloidosis.
- 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 apo A-I
- 5 Factors affecting apo A-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 (protective "fat removal" particles), apo A-I helps to clear fats, including cholesterol, from white blood cells within artery walls, making the 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. One of four mutants of apo A-I is present in roughly 0.3% of the Japanese population, but is found in 6% of those with low HDL cholesterol levels.
ApoA-1 Milano is a naturally occurring mutant of apo A-I, found in a few families in Limone sul Garda, Italy, and, by genetic + church record family tree detective work, traced to a single individual in the 14th century. Described in 1980, it was the first known molecular abnormality of apolipoproteins. 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 apo A-I Milano (the city, Milano, ~160 KM away, in which the researcher's lab was located). Biochemically, apo A-I contains an extra cysteine bridge, causing it to exist as a homodimer or as a heterodimer with apo A-II. However, the enhanced cardioprotective activity of this mutant (which likely depends on fat & cholesterol efflux) cannot easily be replicated by other cysteine mutants.
Recombinant apo A-I Milano dimers formulated into liposomes can reduce atheromas in animal models by up to 30%. Apo A-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.
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 chromosome 11q23, which confer approximately threefold higher risk of coronary heart disease in normal as well as in the patients having non-insulin diabetes mellitus.
Role in other diseases
A G/A polymorphism in the promoter of the apo A-I gene has been associated with the age at which patients presented with Alzheimer disease. Protection from Alzheimer's disease by apo A-I may rely on a synergistic interaction with alpha-tocopherol. Amyloid deposited in the knee following surgery consists largely of apo A-I secreted from chondrocytes (cartilage cells). A wide variety of amyloidosis symptoms are associated with rare Apo A-I mutants.
Epistatic impact of apo A-I
Apolipoprotein A-I and APOE interact epistatically to modulate triglyceride levels in coronary heart disease patients. Individually, neither apo A-I nor apo E was found to be associated with triglyceride (TG) levels however, pairwise epistasis (additive x additive model) explored their significant synergistic contributions with raised TG levels (P<0.01). 
Factors affecting apo A-I activity
Potential binding partners
Apolipoprotein A-I 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. 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.
Apolipoprotein A-I has been shown to interact with:
Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
- The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430".
- 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.
- 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. doi:10.1007/BF00276323. PMID 1972696.
- Halley, Paul; Kadakkuzha, Beena M.; Faghihi, Mohammad Ali, et al. (16 January 2014). "Regulation of the Apolipoprotein Gene Cluster by a Long Noncoding RNA". Cell Reports 6 (1): 222–230. doi:10.1016/j.celrep.2013.12.015. PMID 24388749.
- 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.
- "Entrez Gene: APOA1 apolipoprotein A-I".
- 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 A-I 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.
- "Apo A-I-Milano Trial: Where are we now?". Cleveland Clinic. 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-I Milano". Cedars-Sinai Heart Institute. Retrieved 2008-07-26.[dead link]
- 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): e93–5. 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 non-familial 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 A-I 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): 1118–28. 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 (Epub Ahead) 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".
- Fitzgerald ML, Morris AL, Rhee JS, Andersson LP, Mendez AJ, Freeman MW (September 2002). "Naturally occurring mutations in the largest extracellular loops of ABCA1 can disrupt its direct interaction with apolipoprotein A-I". J. Biol. Chem. 277 (36): 33178–87. doi:10.1074/jbc.M204996200. PMID 12084722.
- Deeg MA, Bierman EL, Cheung MC (March 2001). "GPI-specific phospholipase D associates with an apoA-I- and apoA-IV-containing complex". J. Lipid Res. 42 (3): 442–51. PMID 11254757.
- Pussinen PJ, Jauhiainen M, Metso J, Pyle LE, Marcel YL, Fidge NH, Ehnholm C (January 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. 39 (1): 152–61. PMID 9469594.