Apolipoprotein A1

2017-11-06T02:31:24Z

2603:3013:403:C500:40D0:85D7:B97:E4EB:

{{Infobox_gene}}
'''Apolipoprotein A1''' is a [[protein]] that in humans is encoded by the ''APOA1'' [[gene]].<ref name="pmid6294659">{{cite journal | vauthors = Breslow JL, Ross D, McPherson J, Williams H, Kurnit D, Nussbaum AL, Karathanasis SK, Zannis VI | title = Isolation and characterization of cDNA clones for human apolipoprotein A1 | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 79 | issue = 22 | pages = 6861–5 | date = November 1982 | pmid = 6294659 | pmc = 347233 | doi = 10.1073/pnas.79.22.6861 }}</ref><ref name="pmid1972696">{{cite journal | vauthors = Arinami T, Hirano T, Kobayashi K, Yamanouchi Y, Hamaguchi H | title = Assignment of the apolipoprotein A1 gene to 11q23 based on RFLP in a case with a partial deletion of chromosome 11, del(11)(q23.3----qter) | journal = Hum. Genet. | volume = 85 | issue = 1 | pages = 39–40 | date = June 1990 | pmid = 1972696 | doi = 10.1007/BF00276323 }}</ref> It has a specific role in [[lipid metabolism]]. The text in a recent report suggested that ''APOA1'' mRNA is regulated by endogenously expressed antisense RNA.<ref>{{cite journal | vauthors = Halley P, Kadakkuzha BM, Faghihi MA, Magistri M, Zeier Z, Khorkova O, Coito C, Hsiao J, Lawrence M, Wahlestedt C | title = Regulation of the Apolipoprotein Gene Cluster by a Long Noncoding RNA | journal = Cell Reports | volume = 6 | issue = 1 | pages = 222–230 | date = 16 January 2014 | pmid = 24388749 | doi = 10.1016/j.celrep.2013.12.015 | pmc=3924898}}</ref>

==Structure==
The APOA1 gene is located on the 11th chromosome, with its specific location being 11q23-q24. The gene contains 4 exons.<ref name="entrez" /> APOA1 encodes a 45.4 kDa protein that is composed of 396 amino acids; 21 peptides have been observed through mass spectrometry data.<ref name=COPaKB>{{cite journal | vauthors = Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P | title = Integration of cardiac proteome biology and medicine by a specialized knowledgebase | journal = Circulation Research | volume = 113 | issue = 9 | pages = 1043–53 | date = Oct 2013 | pmid = 23965338 | pmc = 4076475 | doi = 10.1161/CIRCRESAHA.113.301151 }}</ref><ref name="url_COPaKB">{{cite web | url = http://www.heartproteome.org/copa/ProteinInfo.aspx?QType=Protein%20ID&QValue=QP06727 | work = Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) | title = Apolipoprotein A-IV}}</ref>

==Function==
Apolipoprotein A1 is the major protein component of [[high density lipoprotein|HDL]] particles in [[Blood plasma|plasma]].

[[Chylomicron]]s secreted from the intestinal enterocyte also contain apo A1, but it is quickly transferred to HDL in the bloodstream.<ref name="pmid18079757">{{cite journal | vauthors = Wasan KM, Brocks DR, Lee SD, Sachs-Barrable K, Thornton SJ | title = Impact of lipoproteins on the biological activity and disposition of hydrophobic drugs: implications for drug discovery | journal = Nature Reviews Drug Discovery | volume = 7 | issue = 1 | pages = 84–99 | date = January 2008 | pmid = 18079757 | doi = 10.1038/nrd2353 }}</ref>

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|lecithin cholesterolacyltransferase]] (LCAT) which is responsible for the formation of most plasma [[cholesteryl esters]]. Apo A1 was also isolated as a [[prostacyclin]] (PGI2) stabilizing factor, and thus may have an anticlotting effect.<ref>{{cite journal | vauthors = Yui Y, Aoyama T, Morishita H, Takahashi M, Takatsu Y, Kawai C | title = Serum prostacyclin stabilizing factor is identical to apolipoprotein A1 (apo A1). A novel function of apo A1 | journal = J. Clin. Invest. | volume = 82 | issue = 3 | pages = 803–7 | year = 1988 | pmid = 3047170 | pmc = 303586 | doi = 10.1172/JCI113682 }}</ref> Defects in the gene encoding it are associated with HDL deficiencies, including [[Tangier disease]], and with systemic non-neuropathic [[amyloidosis]].<ref name=entrez>{{cite web |title = Entrez Gene: APOA1 apolipoprotein A1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=335| accessdate = }}</ref>

ApoA1 is often used as a biomarker for prediction of cardiovascular diseases. The ratio apoB-100/apoA1 (i.e. LDL & larger particles vs. HDL particles), NMR measured Lipoprotein ([[Low Density Lipoprotein|LDL]]/[[High Density Lipoprotein|HDL]]) particle ratios even more so,<ref>https://www.google.com/search?q=LDL-P+vs.+LDL-C+%26+Cardiovascular+Event+Rates</ref> has always had a stronger correlation with myocardial infarction event rates than older methods of measuring lipid transport in the water outside cells.<ref name="bindingofhdl">{{cite journal | vauthors = McQueen MJ, Hawken S, Wang X, Ounpuu S, Sniderman A, Probstfield J, Steyn K, Sanderson JE, Hasani M, Volkova E, Kazmi K, Yusuf S | title = Lipids, lipoproteins, and apolipoproteins as risk markers of myocardial infarction in 52 countries (the INTERHEART study): a case-control study | journal = Lancet | volume = 372 | issue = 9634 | pages = 224–33 | year = 2008 | pmid = 18640459 | doi = 10.1016/S0140-6736(08)61076-4 }}</ref>

ApoA1 is routinely measured using immunoassays such as [[ELISA]] or [[nephelometry]].

==Clinical significance==

=== 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 A1 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]].<ref name="pmid16023124">{{cite journal | vauthors = Dastani Z, Dangoisse C, Boucher B, Desbiens K, Krimbou L, Dufour R, Hegele RA, Pajukanta P, Engert JC, Genest J, Marcil M | title = A novel nonsense apolipoprotein A-I mutation (apoA-I(E136X)) causes low HDL cholesterol in French Canadians | journal = Atherosclerosis | volume = 185 | issue = 1 | pages = 127–36 | date = March 2006 | pmid = 16023124 | doi = 10.1016/j.atherosclerosis.2005.05.028 }}</ref> One of four mutants of apo A1 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 A1, 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.<ref>http://blogs.sciencemag.org/pipeline/archives/2016/11/16/the-long-saga-of-apo-a1-milano</ref> Described in 1980, it was the first known molecular abnormality of [[apolipoprotein]]s.<ref name="pmid6785551">{{cite journal | vauthors = Franceschini G, Sirtori M, Gianfranceschi G, Sirtori CR | title = Relation between the HDL apoproteins and A-I isoproteins in subjects with the AIMilano abnormality | journal = Metab. Clin. Exp. | volume = 30 | issue = 5 | pages = 502–9 | date = May 1981 | pmid = 6785551 | doi = 10.1016/0026-0495(81)90188-8 }}</ref> 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 A1 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 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.<ref>{{cite journal | vauthors = Zhu X, Wu G, Zeng W, Xue H, Chen B | title = Cysteine mutants of human apolipoprotein A-I: a study of secondary structural and functional properties | journal = J. Lipid Res. | volume = 46 | issue = 6 | pages = 1303–11 | year = 2005 | pmid = 15805548 | doi = 10.1194/jlr.M400401-JLR200 }}</ref>

Recombinant apo A1 Milano dimers formulated into liposomes can reduce [[atheroma]]s in animal models by up to 30%.<ref>{{cite journal | vauthors = Chiesa G, Sirtori CR | title = Apolipoprotein A-I(Milano): current perspectives | journal = Curr. Opin. Lipidol. | volume = 14 | issue = 2 | pages = 159–63 | year = 2003 | pmid = 12642784 | doi = 10.1097/00041433-200304000-00007 }}</ref> Apo A1 Milano has also been shown in small clinical trials to have a statistically significant effect in reducing (reversing) plaque build-up on arterial walls.<ref name="cleveland_clinic">{{cite web | url = http://www.clevelandclinic.org/heartcenter/pub/news/hot/hdlapoa1.asp?firstCat=1&secondCat=429&thirdCat=602 | title = Apo A-I-Milano Trial: Where are we now? | publisher = Cleveland Clinic | pages = | quote = | accessdate = 2008-07-26}}</ref><ref name="pmid14600188">{{cite journal | vauthors = 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 | title = Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial | journal = JAMA | volume = 290 | issue = 17 | pages = 2292–300 | date = November 2003 | pmid = 14600188 | doi = 10.1001/jama.290.17.2292 }}</ref>

In human trials the reversal of plaque build-up was measured over the course of five weeks.<ref name="cleveland_clinic" /><ref name="cedars-sinai">{{cite web|url=http://www.cedars-sinai.edu/pf_6189.html |title=Apo A-I Milano |publisher=Cedars-Sinai Heart Institute |accessdate=2008-07-26 |deadurl=yes |archiveurl=https://web.archive.org/web/20071221232928/http://www.cedars-sinai.edu/pf_6189.html |archivedate=21 December 2007 }}</ref>

===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<ref name="pmid17825930">{{cite journal | vauthors = Singh P, Singh M, Kaur TP, Grewal SS | title = A novel haplotype in ApoAI-CIII-AIV gene region is detrimental to Northwest Indians with coronary heart disease | journal = Int. J. Cardiol. | volume = 130 | issue = 3 | pages = e93–5 | date = September 2007 | pmid = 17825930 | doi = 10.1016/j.ijcard.2007.07.029 }}</ref> as well as in the patients having non-insulin diabetes mellitus.<ref name="pmid17654446">{{cite journal | vauthors = Singh P, Singh M, Gaur S, Kaur T | title = 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 | journal = Diab Vasc Dis Res | volume = 4 | issue = 2 | pages = 124–9 | date = June 2007 | pmid = 17654446 | doi = 10.3132/dvdr.2007.030 }}</ref>

=== Role in other diseases ===

A G/A [[Polymorphism (biology)|polymorphism]] in the [[Promoter (biology)|promoter]] of the apo A1 gene has been associated with the age at which patients presented with [[Alzheimer disease]].<ref>{{cite journal | vauthors = Vollbach H, Heun R, Morris CM, Edwardson JA, McKeith IG, Jessen F, Schulz A, Maier W, Kölsch H | title = APOA1 polymorphism influences risk for early-onset non-familial AD | journal = Ann. Neurol. | volume = 58 | issue = 3 | pages = 436–41 | year = 2005 | pmid = 16130094 | doi = 10.1002/ana.20593 }}</ref> Protection from Alzheimer's disease by apo A1 may rely on a synergistic interaction with [[alpha-tocopherol]].<ref>{{cite journal | vauthors = Maezawa I, Jin LW, Woltjer RL, Maeda N, Martin GM, Montine TJ, Montine KS | title = Apolipoprotein E isoforms and apolipoprotein A-I protect from amyloid precursor protein carboxy terminal fragment-associated cytotoxicity | journal = J. Neurochem. | volume = 91 | issue = 6 | pages = 1312–21 | year = 2004 | pmid = 15584908 | doi = 10.1111/j.1471-4159.2004.02818.x }}</ref>
[[Amyloid]] deposited in the knee following surgery consists largely of apo A1 secreted from [[chondrocytes]] ([[cartilage]] cells).<ref>{{cite journal | vauthors = Solomon A, Murphy CL, Kestler D, Coriu D, Weiss DT, Makovitzky J, Westermark P | title = Amyloid contained in the knee joint meniscus is formed from apolipoprotein A-I | journal = Arthritis Rheum. | volume = 54 | issue = 11 | pages = 3545–50 | year = 2006 | pmid = 17075859 | doi = 10.1002/art.22201 }}</ref> A wide variety of [[amyloidosis]] symptoms are associated with rare Apo A1 mutants.

Apo A-I binds to [[lipopolysaccharide]] or [[endotoxin]], and has a major role in the anti-endotoxin function of HDL.<ref>{{cite journal | vauthors = Ma J, Liao XL, Lou B, Wu MP | title = Role of apolipoprotein A-I in protecting against endotoxin toxicity | journal = Acta Biochim. Biophys. Sin. (Shanghai) | volume = 36 | issue = 6 | pages = 419–24 | year = 2004 | pmid = 15188057 | doi = 10.1093/abbs/36.6.419 }}</ref>

In one study, a decrease in apo A1 levels was detected in [[schizophrenia]] patients' [[Cerebrospinal fluid|CSF]], brain and peripheral tissues.<ref name="pmid17938634">{{cite journal | vauthors = 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 | title = Independent protein-profiling studies show a decrease in apolipoprotein A1 levels in schizophrenia CSF, brain and peripheral tissues | journal = Mol Psychiatry | volume = 13 | issue = 12 | pages = 1118–28 | year = 2007 | pmid = 17938634 | doi = 10.1038/sj.mp.4002108 }}</ref>

=== Epistatic impact of apo A1 ===
Apolipoprotein A1 and APOE interact epistatically to modulate triglyceride levels in coronary heart disease patients. Individually, neither apo A1 nor apo E 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).
<ref>{{cite journal | vauthors = Singh P, Singh M, Kaur T | title = Role of apolipoproteins E and A-I: Epistatic villains of triglyceride mediation in coronary heart disease | journal = Int J Cardiol | volume = 134 | issue = 3 | pages = 410–2 | year = 2008 | pmid = 18378026 | doi = 10.1016/j.ijcard.2007.12.102 }}</ref>

=== Factors affecting apo A1 activity ===

Apo A1 production is decreased by [[calcitriol]], and increased by a drug that antagonizes it.<ref>{{cite journal | vauthors = Wehmeier K, Beers A, Haas MJ, Wong NC, Steinmeyer A, Zugel U, Mooradian AD | title = Inhibition of apolipoprotein AI gene expression by 1, 25-dihydroxyvitamin D3 | journal = Biochim. Biophys. Acta | volume = 1737 | issue = 1 | pages = 16–26 | year = 2005 | pmid = 16236546 | doi = 10.1016/j.bbalip.2005.09.004 }}</ref>

Exercise or [[statin]] treatment may cause an increase in HDL-C levels by inducing apo A1 production, but this depends on the G/A promoter polymorphism.<ref>{{cite journal | vauthors = Lahoz C, Peña R, Mostaza JM, Jiménez J, Subirats E, Pintó X, Taboada M, López-Pastor A | title = Apo A-I promoter polymorphism influences basal HDL-cholesterol and its response to pravastatin therapy | journal = Atherosclerosis | volume = 168 | issue = 2 | pages = 289–95 | year = 2003 | pmid = 12801612 | doi = 10.1016/S0021-9150(03)00094-7 }}</ref>

== Interactions ==
Apolipoprotein A1 has been shown to [[Protein-protein interaction|interact]] with:
* [[ABCA1]],<ref name = pmid12084722>{{cite journal | vauthors = Fitzgerald ML, Morris AL, Rhee JS, Andersson LP, Mendez AJ, Freeman MW | title = Naturally occurring mutations in the largest extracellular loops of ABCA1 can disrupt its direct interaction with apolipoprotein A-I | journal = J. Biol. Chem. | volume = 277 | issue = 36 | pages = 33178–87 | date = September 2002 | pmid = 12084722 | doi = 10.1074/jbc.M204996200 }}</ref>
* [[GPLD1]]<ref name = pmid11254757>{{cite journal | vauthors = Deeg MA, Bierman EL, Cheung MC | title = GPI-specific phospholipase D associates with an apoA-I- and apoA-IV-containing complex | journal = J. Lipid Res. | volume = 42 | issue = 3 | pages = 442–51 | date = March 2001 | pmid = 11254757 | doi = }}</ref> and
* [[PLTP]].<ref name = pmid9469594>{{cite journal | vauthors = Pussinen PJ, Jauhiainen M, Metso J, Pyle LE, Marcel YL, Fidge NH, Ehnholm C | title = 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 | journal = J. Lipid Res. | volume = 39 | issue = 1 | pages = 152–61 | date = January 1998 | pmid = 9469594 | doi = }}</ref>

===Potential binding partners===
Apolipoprotein A1 binding precursor, a relative of APOA-1 abbreviated [[APOA1BP]], has a predicted biochemical interaction with [[CARKD|Carbohydrate Kinase Domain Containing Protein]]. The relationship between these two proteins is substantiated by [[cooccurance across genomes]] and [[coexpression]].<ref name=STRING>{{cite web|title=STRING: Known and Predicted Protein-Protein Interactions |url=http://string.embl.de/newstring_cgi/show_edge_data.pl?taskId=gboDpgqu9YY_&node1=418518&node2=410384 |deadurl=yes |archiveurl=https://web.archive.org/web/20110718103541/http://string.embl.de/newstring_cgi/show_edge_data.pl?taskId=gboDpgqu9YY_&node1=418518&node2=410384 |archivedate=18 July 2011 }}</ref> 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.

===Interactive pathway map===
{{StatinPathway_WP430|highlight=Apolipoprotein_A1}}

== See also ==
* [[Apolipoprotein B]]
* [[Cardiovascular disease]]
* [[ApoA-1 Milano]]

== References ==
{{Reflist|2}}

== External links ==
* {{MeshName|Apolipoprotein+A-I}}
* [https://www.mabtech.com/knowledge-center/applied-research/apolipoproteins Applied Research on Apolipoprotein-A1]
* {{UCSC gene info|APOA1}}

{{Lipoproteins}}

{{Use dmy dates|date=March 2012}}

[[Category:Apolipoproteins]]

[[zh:载脂蛋白]]

wikidoc - User contributions [en]

Apolipoprotein A1