Apolipoprotein A1

Apolipoprotein A-I, also known as APOA1, is a human gene.

The protein encoded by this gene is an apolipoprotein. It is the major protein component of high density lipoprotein (HDL) in plasma. The protein promotes cholesterol efflux 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. ApoA-I was also isolated as a prostacyclin (PGI2) stabilizing factor, and thus may have an anticlotting effect. [cite journal |author=Yui Y, Aoyama T, Morishita H, Takahashi M, Takatsu Y, Kawai C |title=Serum prostacyclin stabilizing factor is identical to apolipoprotein A-I (Apo A-I). A novel function of Apo A-I |journal=J. Clin. Invest. |volume=82 |issue=3 |pages=803–7 |year=1988 |pmid=3047170 |doi=10.1172/JCI113682] Defects in the gene encoding it are associated with HDL deficiencies, including Tangier disease, and with systemic non-neuropathic amyloidosis. [cite web | title = Entrez Gene: APOA1 apolipoprotein A-I| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=335| accessdate = ]

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.cite journal | author = 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 | year = 2006 | month = March | pmid = 16023124 | doi = 10.1016/j.atherosclerosis.2005.05.028 | url = | issn = ] 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-I 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.cite journal | author = Franceschini G, Sirtori M, Gianfranceschi G, Sirtori CR | title = Relation between the HDL apoproteins and AI isoproteins in subjects with the AIMilano abnormality | journal = Metab. Clin. Exp. | volume = 30 | issue = 5 | pages = 502–9 | year = 1981 | month = May | pmid = 6785551 | doi = 10.1016/0026-0495(81)90188-8 | url = | issn = ] 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. [cite journal |author=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]

Recombinant Apo-I Milano dimers formulated into liposomes can reduce atheromas in animal models by up to 30%. [cite journal |author=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] 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.cite web | url = http://www.clevelandclinic.org/heartcenter/pub/news/hot/hdlapoa1.asp?firstCat=1&secondCat=429&thirdCat=602 | title = Apo A1-Milano Trial: Where are we now? | author = | authorlink = | coauthors = | date = | format = | work = | publisher = Cleveland Clinic | pages = | language = | archiveurl = | archivedate = | quote = | accessdate = 2008-07-26] cite journal | author = 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 | year = 2003 | month = November | pmid = 14600188 | doi = 10.1001/jama.290.17.2292 | url = | issn = ]

In human trials the reversal of plaque build-up was measured over the course of five weeks.cite web | url = http://www.cedars-sinai.edu/pf_6189.html | title = Apo A-1 Milano | author = | authorlink = | coauthors = | date = | format = | work = | publisher = Cedars-Sinai Heart Institute | pages = | language = | archiveurl = | archivedate = | quote = | accessdate = 2008-07-26]

APP018 (formerly D-4F), an 18-amino acid peptide (Ac-D-W-F-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F-NH2 [US patent reference | number = 7144862 | y = 2003 | m = 09 | d = 11 | inventor = Fogelman AM, Anantharamaiah GM, Navab M | title = Orally administered peptides to ameliorate atherosclerosis. ] [Ref patent | country = WO | number = 2006118805 | status = application
title = Peptides and peptide mimetics to treat pathologies characterized by an inflammatory response | pubdate = 2006-11-09 | invent1 = Fogelman AM | invent2 = Navab M | assign1 = University of California ] (using D-amino acids) that can be taken orally, was developed by Bruin Pharmaceuticals (a little-known company founded by Dr. Alan Fogelman, named after the UCLA Bruinscite web | url = http://www.forbes.com/sciencesandmedicine/2005/07/08/novartis-cholesterol-HDL-cx_mh_0711nvshdl4.html | title = Novartis Enters 'Good Cholesterol' Battle | author = Herper M | authorlink = | coauthors = | date = 2005-07-11 | format = | work = | publisher = Forbes.com | pages = | language = | archiveurl = | archivedate = | quote = | accessdate = 2008-07-26] cite web | url = http://www.fiercebiotech.com/Fierce15/2006/bruin.asp | title = Bruin Pharmaceuticals | author = | authorlink = | coauthors = | date = | format = | work = | publisher = FierceBiotech | pages = | language = | archiveurl = | archivedate = | quote = | accessdate = 2008-07-26] and sold to Novartis for $200 million USD. The peptide and close variations thereof such as D-5F have been shown to elevate HDL-C and reduce atherosclerotic build-up in early animal data. The peptide has been tested with a variety of modifications, formulated with an excipient such as poly(lactide-co-glycolide) (PLG), and formed into ProLease drug-polymer microspheres.cite journal | author = Bartus RT, Tracy MA, Emerich DF, Zale SE | title = Sustained delivery of proteins for novel therapeutic agents | journal = Science (journal) | volume = 281 | issue = 5380 | pages = 1161–2 | year = 1998 | month = August | pmid = 9735031 | doi = 10.1126/science.281.5380.1161 | url = | issn = ] If all continues to go well it is expected to reach the pharmacy shelf around 2013.cite web | url = http://www.biomarketgroup.com/content/view/82/7/ | title = BioMarket Group - Antidyslipidemics: market set for contraction as generics hit hard | author = | authorlink = | coauthors = | date = 2006-10-04 | format = | work = | publisher = BioMarket Group | pages = | language = | archiveurl = | archivedate = | quote = | accessdate = 2008-07-26]

* 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, who confer approximately threefold higher risk of coronary heart disease in normalcite journal | author = 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 = | issue = | pages = | year = 2007 | month = September | pmid = 17825930 | doi = 10.1016/j.ijcard.2007.07.029 | url = | issn = | accessdate = 2008-07-26] as well as non-insulin diabetes mellitus.cite journal | author = 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 | year = 2007 | month = June | pmid = 17654446 | doi = 10.3132/dvdr.2007.030 | url = | issn = | accessdate = 2008-07-26]

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. [cite journal |author=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 nonfamiliar AD |journal=Ann. Neurol. |volume=58 |issue=3 |pages=436–41 |year=2005 |pmid=16130094 |doi=10.1002/ana.20593] Protection from Alzheimer disease by ApoA1 may rely on a synergistic interaction with alpha-tocopherol. [cite journal |author=Maezawa I, Jin LW, Woltjer RL, Maeda N, Martin GM, Montine TJ, Montine KS |title=Apolipoprotein E isoforms and apolipoprotein AI 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] Apolipoprotein A-I and APOE interact epistatically to modulate triglyceride levels in Coronary Heart Disease patients. [cite journal |author=SinghP, SinghM, Kaur T|title=Role of apolipoproteins E and A-I: Epistatic villains of triglyceride mediation in coronary heart disease. |journal=Int J Cardiol|Epub Ahead |year=2008 |pmid=18378026 |]
Amyloid deposited in the knee following surgery consists largely of ApoA-I secreted from chondrocytes (cartilage cells). [cite journal |author=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] 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. [cite journal |author=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]

In one study, a decrease in ApoA1 levels was detected in schizophrenia patients' CSF, brain and peripheral tissues. cite journal |author=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= |issue= |pages= |year=2007 |pmid=17938634 |doi=10.1038/sj.mp.4002108]

Factors affecting ApoA-I activity

ApoA-I production is decreased by Vitamin D, and increased by a drug that antagonizes it. [cite journal |author=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]

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. [cite journal |author=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]

References

External links

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