Apolipoprotein A1
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]
| Apolipoprotein A-I | |||||||||||||
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 PDB rendering based on 1av1. | |||||||||||||
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| Symbols | APOA1 ; MGC117399 | ||||||||||||
| External IDs | Template:OMIM5 Template:MGI HomoloGene: 47900 | ||||||||||||
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Overview
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.
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 [3] as well as non-insulin diabetes mellitus[4].
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 [5] as well as non-insulin diabetes mellitus[6].
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. 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. 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. PMID 15805548.
- ↑ Chiesa G, Sirtori CR (2003). "Apolipoprotein A-I(Milano): current perspectives". Curr. Opin. Lipidol. 14 (2): 159–63. PMID 12642784.
- ↑ 6.0 6.1 "Apo A1-Milano Trial: Where are we now?". Cleveland Clinic. Retrieved 2006-11-09.
- ↑ "Cedars-Sinai Heart Center - Apo A-1 Milano". Cedars-Sinai Heart Center. Retrieved 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, "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. 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. 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. 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:10.1038/sj.mp.4002108. 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. PMID 12801612.
External links
- Apolipoprotein+A-I at the US National Library of Medicine Medical Subject Headings (MeSH)