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Apolipoprotein A-I
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| PDB rendering based on 1av1. | ||||||||||||||
| Available structures: 1av1, 1gw3, 1gw4, 2a01 | ||||||||||||||
| Identifiers | ||||||||||||||
| Symbol(s) | APOA1; MGC117399 | |||||||||||||
| External IDs | OMIM: 107680 MGI: 88049 HomoloGene: 47900 | |||||||||||||
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| RNA expression pattern | ||||||||||||||
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| Orthologs | ||||||||||||||
| Human | Mouse | |||||||||||||
| Entrez | 335 | 11806 | ||||||||||||
| Ensembl | ENSG00000118137 | ENSMUSG00000032083 | ||||||||||||
| Uniprot | P02647 | O08855 | ||||||||||||
| Refseq | NM_000039 (mRNA) NP_000030 (protein) |
NM_009692 (mRNA) NP_033822 (protein) |
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| Location | Chr 11: 116.21 - 116.21 Mb | Chr 9: 45.98 - 45.98 Mb | ||||||||||||
| Pubmed search | [2] | [3] | ||||||||||||
Apolipoprotein A-I (ApoA-I) 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.[1] Defects in the gene encoding it are associated with HDL deficiencies, including Tangier disease, and with systemic non-neuropathic amyloidosis.
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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.[2] 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.[3] 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.[4]
Recombinant Apo-I Milano dimers formulated into liposomes can reduce atheromas in animal models by up to 30%.[5] ApoA-I Milano has also been shown in small clinical trials to have a statistically significant[6] effect in reducing (reversing) plaque build-up on arterial walls. In human trials the reversal of plaque build-up was measured over the course of five weeks.[6][7]
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[8][9], 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 Bruins[10][11]) 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[12] drug-polymer microspheres. If all continues to go well it is expected to reach the pharmacy shelf around 2013.[13]
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 normal [4] as well as non-insulin diabetes mellitus[5].
June 18, 2008, San Diego, CA and Calgary, AB – Resverlogix Corp. (“Resverlogix” or the "Company") (TSX:RVX) announced today that it has completed the planned exploratory efficacy analysis of the data from the Phase I, 7 day RVX-208 treatment subjects. Analysis from two independent and external laboratories of blinded serum samples showed consistent improvements of key biomarkers for the RCT (reverse cholesterol transport) pathway. “Analysis from 24 healthy volunteers in the 7 day RVX-208 trial showed statistically significant improvements over placebo in 3 of the 4 key variables assessed,” stated Donald J. McCaffrey, President & CEO of Resverlogix. A fourth variable also showed positive trending but was not validated as statistically significant. McCaffrey emphasized, “All other lipid parameters behaved as anticipated. As efficacy is the one of the goals of our upcoming 28 day Phase 1b/2a trial we are very pleased to see the primary indicators behaving as they did. We were especially pleased to see the increases in pre-beta HDL of in excess of 30%, cholesterol efflux above 10%, serum ApoAl above 10%, and HDL-C above 10% (not statistically significant) versus placebo. This follows a very similar improvement pattern as previously demonstrated by Resverlogix in the African Green Monkey studies. Crucial to these findings is the rapid onset of action in this 7 day trial, with the serum ApoA-I increases surpassing the previous 8% five week (35 day) average benchmark totals displayed by Pfizer’s previous ApoA-I Milano recombinant protein studies.” McCaffrey continued, “What has been truly unique about RVX-208 versus other small molecule HDL/ApoA-I programs is that RVX-208 facilitates endogenous ApoA-I production. Resverlogix now has a commanding lead in the development of atherosclerosis therapeutics. To our knowledge no other small molecules, whether it is the statins, other HDL drugs or lipid modifying programs have demonstrated HDL functionality and RCT.” RCT is a pathway by which accumulated cholesterol is transported from the arterial wall to the liver for excretion, thus preventing atherosclerosis. Major constituents of RCT include acceptors such as high-density lipoprotein (HDL) and apolipoprotein A-I (ApoA-I). A critical part of RCT is cholesterol efflux, in which accumulated cholesterol is removed from macrophages. Resverlogix will be presenting at the BIO Business Forum held in San Diego, California on Thursday June 19, 2008 at 1:15pm PDT in Room 4. About Resverlogix Corp. Resverlogix Corp. is a leading biotechnology company engaged in the development of novel therapies for important global medical markets with significant unmet needs. The NexVas™ program is the Company’s primary focus which is to develop novel small molecules that enhance ApoA-I. These vital therapies address the grievous burden of atherosclerosis and other important diseases such as acute coronary syndrome, diabetes, Alzheimer’s and other vascular disorders. The Company’s secondary focus is TGF-Beta Shield™, a program that aims to address burgeoning grievous diseases, such as cancer and fibrosis. Resverlogix Corp. trades on the Toronto Stock Exchange (TSX:RVX). For further information please visit www.resverlogix.com.
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.[14] Protection from Alzheimer disease by ApoA1 may rely on a synergistic interaction with alpha-tocopherol[15].
Amyloid deposited in the knee following surgery consists largely of ApoA-I secreted from chondrocytes (cartilage cells).[16] 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.[17]
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 normal [6] as well as non-insulin diabetes mellitus[7].
In one study, a decrease in ApoA1 levels was detected in schizophrenia patients' CSF, brain and peripheral tissues.[18]
Factors affecting ApoA-I activity
ApoA-I production is decreased by Vitamin D, and increased by a drug that antagonizes it.[19]
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.[20]
References
- ^ 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:. PMID 3047170.
- ^ Dastani Z, Dangoisse C, Boucher B, Desbiens K, Krimbou L, Dufour R, Hegele RA, Pajukanta P, Engert JC, Genest J, Marcil M (2006). "A novel nonsense apolipoprotein A-I mutation (apoA-I(E136X)) causes low HDL cholesterol in French Canadians". Atherosclerosis 185 (1): 127–36. doi:. PMID 16023124.
- ^ Franceschini G, Sirtori M, Gianfranceschi G, Sirtori CR (1981). "Relation between the HDL apoproteins and AI isoproteins in subjects with the AIMilano abnormality". Metab. Clin. Exp. 30 (5): 502–9. 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:. PMID 15805548.
- ^ Chiesa G, Sirtori CR (2003). "Apolipoprotein A-I(Milano): current perspectives". Curr. Opin. Lipidol. 14 (2): 159–63. doi:. PMID 12642784.
- ^ a b "Apo A1-Milano Trial: Where are we now?". Cleveland Clinic. Retrieved on 2006-11-09.
- ^ "Cedars-Sinai Heart Center - Apo A-1 Milano". Cedars-Sinai Heart Center. Retrieved on 2006-11-09.
- ^ Patent US 7,144,862 B2
- ^ Patent WO2006 118805
- ^ Matthew Herper, Forbes 07.11.05 "Novartis Enters 'Good Cholesterol' Battle."
- ^ Fierce Biotech. "Bruin Pharmaceuticals."
- ^ Bartus et al., 1998, Science 281:1161-2 [1]
- ^ BioMarket Group AB, I believe Novartis has stopped development work on this compound."Antidyslipidemics: market set for contraction as generics hit hard", October 4, 2006.
- ^ 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:. 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:. 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:. 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. 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. doi:. PMID 17938634.
- ^ 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. 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:. PMID 12801612.
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