Apolipoprotein AI explained

Apolipoprotein AI (Apo-AI) is a protein that in humans is encoded by the APOA1 gene.[1] [2] As the major component of HDL particles, it has a specific role in lipid metabolism.

Structure

APOA1 is located on chromosome 11, with its specific location being 11q23-q24. The gene contains 4 exons. The encoded apolipoprotein AI, is a 28.1 kDa protein composed of 243 amino acids; 21 peptides have been observed through mass spectrometry data.[3] [4] Due to alternative splicing, there exists multiple transcript variants of APOA1, including at least one which encodes a Apo-AI preprotein.

Function

Apolipoprotein AI is the major protein component of high density lipoprotein (HDL) particles in plasma.[5]

Chylomicrons secreted from the intestinal enterocyte also contain Apo-AI, but it is quickly transferred to HDL in the bloodstream.[6]

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 (LCAT) which is responsible for the formation of most plasma cholesteryl esters. Apolipoprotein AI has also been isolated as a prostacyclin (PGI2) stabilizing factor, and thus may have an anticlotting effect.[7] Defects in the gene encoding it are associated with HDL deficiencies, including Tangier disease, and with systemic non-neuropathic amyloidosis.[8]

Apo-AI is often used as a biomarker for prediction of cardiovascular diseases. The ratio apoB-100/apoA-I (i.e. LDL & larger particles vs. HDL particles), NMR measured lipoprotein (low density lipoprotein (LDL)/(HDL) particle ratios even more so, has always had a stronger correlation with myocardial infarction event rates than older methods of measuring lipid transport in the water outside cells.[9]

Apo-AI is routinely measured using immunoassays such as ELISA or nephelometry.

Applications

Apo-AI can be used to create in vitro lipoprotein nanodiscs for cell-free membrane expression systems.[10]

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-AI helps to clear fats, including cholesterol, from white blood cells within artery walls, making the white blood cells (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.[11] One of four mutants of Apo-AI is present in roughly 0.3% of the Japanese population, but is found in 6% of those with low HDL cholesterol levels.[12]

ApoA-I Milano is a naturally occurring mutant of Apo-AI, 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.[13] Described in 1980, it was the first known molecular abnormality of apolipoproteins.[14] 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 apoA-I 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-AII. However, the enhanced cardioprotective activity of this mutant (which likely depends on fat & cholesterol efflux) cannot easily be replicated by other cysteine mutants.[15]

Recombinant Apo-AI Milano dimers formulated into liposomes can reduce atheromas in animal models by up to 30%.[16] Apo-AI Milano has also been shown in small clinical trials to have a statistically significant effect in reducing (reversing) plaque build-up on arterial walls.[17] [18]

In human trials the reversal of plaque build-up was measured over the course of five weeks.[19]

Novel haplotypes within apolipoprotein AI-CIII-AIV gene cluster

A study from 2008 describes two novel susceptibility haplotypes, P2-S2-X1 and P1-S2-X1, discovered in ApoAI-CIII-AIV gene cluster on chromosome 11q23, which confer approximately threefold higher risk of coronary heart disease in normal[20] as well as in the patients having type 2 diabetes mellitus.[21]

Role in other diseases

A G/A polymorphism in the promoter of the APOA1 gene has been associated with the age at which Alzheimer disease is presented.[22] Protection from Alzheimer's disease by Apo-AI may rely on a synergistic interaction with alpha-tocopherol.[23] Amyloid deposited in the knee following surgery consists largely of Apo-AI secreted from chondrocytes (cartilage cells).[24] A wide variety of amyloidosis symptoms are associated with rare APOA1 mutants.

Apo-AI binds to lipopolysaccharide or endotoxin, and has a major role in the anti-endotoxin function of HDL.[25]

In one study, a decrease in Apo-AI levels was detected in schizophrenia patients' CSF, brain and peripheral tissues.[26]

Epistatic impact of Apo-AI

Apolipoprotein AI and ApoE interact epistatically to modulate triglyceride levels in coronary heart disease patients. Individually, neither Apo-AI nor ApoE 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).[27]

Factors affecting Apo-AI activity

In a study from 2005 it was reported, that Apo-AI production is decreased by calcitriol. It was concluded, that this regulation happens on transcription level: calcitriol alters yet unknown coactivators or corepressors, resulting in repression of APOA1 promoter activity. Simultaneously, Apo-AI production was increased by vitamin D antagonist, ZK-191784.[28]

Exercise or statin treatment may cause an increase in HDL-C levels by inducing Apo-AI production, but this depends on the G/A promoter polymorphism.[29]

Interactions

Apolipoprotein A1 has been shown to interact with:

Potential binding partners

Apolipoprotein AI 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.[33] 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

See also

External links

Notes and References

  1. Breslow JL, Ross D, McPherson J, Williams H, Kurnit D, Nussbaum AL, Karathanasis SK, Zannis VI . Isolation and characterization of cDNA clones for human apolipoprotein A-I . Proceedings of the National Academy of Sciences of the United States of America . 79 . 22 . 6861–6865 . November 1982 . 6294659 . 347233 . 10.1073/pnas.79.22.6861 . free . 1982PNAS...79.6861B .
  2. Arinami T, Hirano T, Kobayashi K, Yamanouchi Y, Hamaguchi H . 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) . Human Genetics . 85 . 1 . 39–40 . June 1990 . 1972696 . 10.1007/BF00276323 . 22613512 .
  3. 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 . Integration of cardiac proteome biology and medicine by a specialized knowledgebase . Circulation Research . 113 . 9 . 1043–1053 . October 2013 . 23965338 . 4076475 . 10.1161/CIRCRESAHA.113.301151 .
  4. Web site: Apolipoprotein A-IV . Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) . 25 March 2015 . https://web.archive.org/web/20160305171156/http://heartproteome.org/copa/proteininfo.aspx?qtype=protein%20id&qvalue=qp06727 . 5 March 2016 . dead .
  5. Book: van der Vorst EP. Vertebrate and Invertebrate Respiratory Proteins, Lipoproteins and other Body Fluid Proteins . High-Density Lipoproteins and Apolipoprotein A1 . Subcellular Biochemistry . 94 . 399–420 . 2020 . 10.1007/978-3-030-41769-7_16 . 32189309. 978-3-030-41768-0 . 213180689 .
  6. Wasan KM, Brocks DR, Lee SD, Sachs-Barrable K, Thornton SJ . Impact of lipoproteins on the biological activity and disposition of hydrophobic drugs: implications for drug discovery . Nature Reviews. Drug Discovery . 7 . 1 . 84–99 . January 2008 . 18079757 . 10.1038/nrd2353 . 1989187 .
  7. Yui Y, Aoyama T, Morishita H, Takahashi M, Takatsu Y, Kawai C . Serum prostacyclin stabilizing factor is identical to apolipoprotein A-I (Apo A-I). A novel function of Apo A-I . The Journal of Clinical Investigation . 82 . 3 . 803–807 . September 1988 . 3047170 . 303586 . 10.1172/JCI113682 .
  8. Web site: Entrez Gene: APOA1 apolipoprotein A1.
  9. McQueen MJ, Hawken S, Wang X, Ounpuu S, Sniderman A, Probstfield J, Steyn K, Sanderson JE, Hasani M, Volkova E, Kazmi K, Yusuf S . Lipids, lipoproteins, and apolipoproteins as risk markers of myocardial infarction in 52 countries (the INTERHEART study): a case-control study . Lancet . 372 . 9634 . 224–233 . July 2008 . 18640459 . 10.1016/S0140-6736(08)61076-4 . 26567691 .
  10. Shelby ML, He W, Dang AT, Kuhl TL, Coleman MA . Cell-Free Co-Translational Approaches for Producing Mammalian Receptors: Expanding the Cell-Free Expression Toolbox Using Nanolipoproteins . Frontiers in Pharmacology . 10 . 744 . 2019-07-03 . 31333463 . 6616253 . 10.3389/fphar.2019.00744 . Frontiers Media SA . free .
  11. Dastani Z, Dangoisse C, Boucher B, Desbiens K, Krimbou L, Dufour R, Hegele RA, Pajukanta P, Engert JC, Genest J, Marcil M . A novel nonsense apolipoprotein A-I mutation (apoA-I(E136X)) causes low HDL cholesterol in French Canadians . Atherosclerosis . 185 . 1 . 127–136 . March 2006 . 16023124 . 10.1016/j.atherosclerosis.2005.05.028 .
  12. Yamakawa-Kobayashi K, Yanagi H, Fukayama H, Hirano C, Shimakura Y, Yamamoto N, Arinami T, Tsuchiya S, Hamaguchi H . Frequent occurrence of hypoalphalipoproteinemia due to mutant apolipoprotein A-I gene in the population: a population-based survey . Human Molecular Genetics . 8 . 2 . 331–336 . February 1999 . 9931341 . 10.1093/hmg/8.2.331 .
  13. Web site: The Long Saga of Apo-A1 Milano | in the Pipeline. 16 November 2016.
  14. Franceschini G, Sirtori M, Gianfranceschi G, Sirtori CR . Relation between the HDL apoproteins and AI isoproteins in subjects with the AIMilano abnormality . Metabolism . 30 . 5 . 502–509 . May 1981 . 6785551 . 10.1016/0026-0495(81)90188-8 .
  15. Zhu X, Wu G, Zeng W, Xue H, Chen B . Cysteine mutants of human apolipoprotein A-I: a study of secondary structural and functional properties . Journal of Lipid Research . 46 . 6 . 1303–1311 . June 2005 . 15805548 . 10.1194/jlr.M400401-JLR200 . free .
  16. Chiesa G, Sirtori CR . Apolipoprotein A-I(Milano): current perspectives . Current Opinion in Lipidology . 14 . 2 . 159–163 . April 2003 . 12642784 . 10.1097/00041433-200304000-00007 . 75941726 .
  17. Web site: Apo A-I-Milano Trial: Where are we now? . Cleveland Clinic . 2008-07-26.
  18. 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 . Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial . JAMA . 290 . 17 . 2292–2300 . November 2003 . 14600188 . 10.1001/jama.290.17.2292 . free .
  19. Web site: Apo A-I Milano . Cedars-Sinai Heart Institute . 2008-07-26 . dead . https://web.archive.org/web/20071221232928/http://www.cedars-sinai.edu/pf_6189.html . 21 December 2007 .
  20. Singh P, Singh M, Kaur TP, Grewal SS . A novel haplotype in ApoAI-CIII-AIV gene region is detrimental to Northwest Indians with coronary heart disease . International Journal of Cardiology . 130 . 3 . e93–e95 . November 2008 . 17825930 . 10.1016/j.ijcard.2007.07.029 .
  21. Singh P, Singh M, Gaur S, Kaur T . 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 . Diabetes & Vascular Disease Research . 4 . 2 . 124–129 . June 2007 . 17654446 . 10.3132/dvdr.2007.030 . 23793589 .
  22. Vollbach H, Heun R, Morris CM, Edwardson JA, McKeith IG, Jessen F, Schulz A, Maier W, Kölsch H . APOA1 polymorphism influences risk for early-onset nonfamiliar AD . Annals of Neurology . 58 . 3 . 436–441 . September 2005 . 16130094 . 10.1002/ana.20593 . 42148248 .
  23. Maezawa I, Jin LW, Woltjer RL, Maeda N, Martin GM, Montine TJ, Montine KS . Apolipoprotein E isoforms and apolipoprotein AI protect from amyloid precursor protein carboxy terminal fragment-associated cytotoxicity . Journal of Neurochemistry . 91 . 6 . 1312–1321 . December 2004 . 15584908 . 10.1111/j.1471-4159.2004.02818.x . 30014992 .
  24. Solomon A, Murphy CL, Kestler D, Coriu D, Weiss DT, Makovitzky J, Westermark P . Amyloid contained in the knee joint meniscus is formed from apolipoprotein A-I . Arthritis and Rheumatism . 54 . 11 . 3545–3550 . November 2006 . 17075859 . 10.1002/art.22201 .
  25. Ma J, Liao XL, Lou B, Wu MP . Role of apolipoprotein A-I in protecting against endotoxin toxicity . Acta Biochimica et Biophysica Sinica . 36 . 6 . 419–424 . June 2004 . 15188057 . 10.1093/abbs/36.6.419 .
  26. 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 . Independent protein-profiling studies show a decrease in apolipoprotein A1 levels in schizophrenia CSF, brain and peripheral tissues . Molecular Psychiatry . 13 . 12 . 1118–1128 . December 2008 . 17938634 . 10.1038/sj.mp.4002108 . 5576909 . free .
  27. Singh P, Singh M, Kaur T . Role of apolipoproteins E and A-I: epistatic villains of triglyceride mediation in coronary heart disease . International Journal of Cardiology . 134 . 3 . 410–412 . May 2009 . 18378026 . 10.1016/j.ijcard.2007.12.102 .
  28. Wehmeier K, Beers A, Haas MJ, Wong NC, Steinmeyer A, Zugel U, Mooradian AD . Inhibition of apolipoprotein AI gene expression by 1, 25-dihydroxyvitamin D3 . Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids . 1737 . 1 . 16–26 . October 2005 . 16236546 . 10.1016/j.bbalip.2005.09.004 .
  29. Lahoz C, Peña R, Mostaza JM, Jiménez J, Subirats E, Pintó X, Taboada M, López-Pastor A . Apo A-I promoter polymorphism influences basal HDL-cholesterol and its response to pravastatin therapy . Atherosclerosis . 168 . 2 . 289–295 . June 2003 . 12801612 . 10.1016/S0021-9150(03)00094-7 .
  30. Fitzgerald ML, Morris AL, Rhee JS, Andersson LP, Mendez AJ, Freeman MW . Naturally occurring mutations in the largest extracellular loops of ABCA1 can disrupt its direct interaction with apolipoprotein A-I . The Journal of Biological Chemistry . 277 . 36 . 33178–33187 . September 2002 . 12084722 . 10.1074/jbc.M204996200 . free .
  31. Deeg MA, Bierman EL, Cheung MC . GPI-specific phospholipase D associates with an apoA-I- and apoA-IV-containing complex . Journal of Lipid Research . 42 . 3 . 442–451 . March 2001 . 11254757 . 10.1016/S0022-2275(20)31669-2 . free .
  32. Pussinen PJ, Jauhiainen M, Metso J, Pyle LE, Marcel YL, Fidge NH, Ehnholm C . 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 of Lipid Research . 39 . 1 . 152–161 . January 1998 . 9469594 . 10.1016/S0022-2275(20)34211-5 . free .
  33. Web site: STRING: Known and Predicted Protein-Protein Interactions . dead . https://web.archive.org/web/20110718103541/http://string.embl.de/newstring_cgi/show_edge_data.pl?taskId=gboDpgqu9YY_&node1=418518&node2=410384 . 18 July 2011 .

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