载脂蛋白A1
載脂蛋白A1（英語：Apolipoprotein A1，簡稱ApoA1）為附著於高密度脂蛋白（HDL）及乳靡小球上的載脂蛋白，基因編碼為「APOA1」[1][2]。載脂蛋白A1可以活化卵磷脂-胆固醇酰基转移酶（Lecithin Cholesterol Acyltransferase，LCAT）；當高密度脂蛋白運送組織中多餘的膽固醇回到肝臟細胞中時，載脂蛋白A1同時也可作為高密度脂蛋白的配體，在脂質代謝中扮演重要角色。研究指出，APOA1的mRNA是由反義RNA轉譯出的內源性蛋白質所調控[3]。
結構
[编辑]APOA1基因位於第11對染色體上（11q23-q24），該基因包含4個外顯子[4]。载脂蛋白A1的質量為45.4 kDa ，含有 396 個胺基酸；質譜分析可觀察到蛋白質由21個胜肽片段組成[5][6]。
功能
[编辑]載脂蛋白A1（ApoA1）為構成血漿中高密度脂蛋白（HDL）蛋白質部分的主要成分。小腸腸道細胞所分泌的乳糜微粒中雖然也含有載脂蛋白A1，但在血流中很快就會被轉為HDL[7]。ApoA1可促進將周邊組織脂質及膽固醇回收至肝臟，並藉由膽管分泌至小腸。另外該蛋白也是卵磷脂-胆固醇酰基转移酶（LCAT）的輔因子，製造了血漿中大多數的膽固醇脂。ApoA1同時也是前列环素（PGI2）的穩定因子，因此也具有抗凝血的作用[8]。如果編碼該蛋白的基因有缺陷，會導致個體體內缺乏HDL，導致包含Tangier disease在內的症狀，以及非神經性全身類澱粉變性[4]。
由於ApoA1在體內脂質代謝的角色相當重要，因此常被視為預測個體冠心病風險的生物標記。有研究發現「apoB-100/apoA1」的比值預測心肌梗塞的效果比任何其他脂質標記更有效果[9]。ApoA1可利用ELISA或nephelometry檢驗。
臨床意義
[编辑]Activity associated with high HDL-C and protection from heart disease
[编辑]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.[10]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 in the 14th century. Described in 1980, it was the first known molecular abnormality of apolipoproteins.[11]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.[12]
Recombinant apo A1 Milano dimers formulated into liposomes can reduce atheromas in animal models by up to 30%.[13]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.[14][15]
In human trials the reversal of plaque build-up was measured over the course of five weeks.[14][16]
Novel Haplotypes within apolipoprotein AI-CIII-AIV gene cluster
[编辑]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[17]as well as in the patients having non-insulin diabetes mellitus.[18]
Role in other diseases
[编辑]A G/A polymorphism in the promoter of the apo A1 gene has been associated with the age at which patients presented with Alzheimer disease.[19]Protection from Alzheimer's disease by apo A1 may rely on a synergistic interaction with alpha-tocopherol.[20] Amyloid deposited in the knee following surgery consists largely of apo A1 secreted from chondrocytes (cartilage cells).[21]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.[22]
In one study, a decrease in apo A1 levels was detected in schizophrenia patients' CSF, brain and peripheral tissues.[23]
Epistatic impact of apo A1
[编辑]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). [24]
Factors affecting apo A1 activity
[编辑]Apo A1 production is decreased by calcitriol, and increased by a drug that antagonizes it.[25]
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.[26]
交互作用
[编辑]載脂蛋白A1可與下列蛋白產生交互作用：
Potential binding partners
[编辑]Apolipoprotein A1 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.[30]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.
交互作用途徑
[编辑]点击基因、蛋白质和代谢产物的链接访问对应的介绍条目。 [§ 1]
- ^ 这个相互作用途径可以在WikiPathways上编辑: Statin_Pathway_WP430.
參見
[编辑]參考文獻
[编辑]- ^ 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. Proc. Natl. Acad. Sci. U.S.A. November 1982, 79 (22): 6861–5. PMC 347233
. PMID 6294659. doi:10.1073/pnas.79.22.6861.
- ^ 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). Hum. Genet. June 1990, 85 (1): 39–40. PMID 1972696. doi:10.1007/BF00276323.
- ^ Halley P, Kadakkuzha BM, Faghihi MA, Magistri M, Zeier Z, Khorkova O, Coito C, Hsiao J, Lawrence M, Wahlestedt C. Regulation of the Apolipoprotein Gene Cluster by a Long Noncoding RNA. Cell Reports. 16 January 2014, 6 (1): 222–230. PMID 24388749. doi:10.1016/j.celrep.2013.12.015.
- ^ 4.0 4.1 Entrez Gene: APOA1 apolipoprotein A1. （原始内容存档于2019-10-16）.
- ^ ]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. Oct 2013, 113 (9): 1043–53. PMC 4076475 . PMID 23965338. doi:10.1161/CIRCRESAHA.113.301151.
- ^ Apolipoprotein A-IV. Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). [2016-08-13]. （原始内容存档于2016-03-05）.
- ^ 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. January 2008, 7 (1): 84–99. PMID 18079757. doi:10.1038/nrd2353.
- ^ Yui Y, Aoyama T, Morishita H, Takahashi M, Takatsu Y, Kawai C. Serum prostacyclin stabilizing factor is identical to apolipoprotein A1 (apo A1). A novel function of apo A1. J. Clin. Invest. 1988, 82 (3): 803–7. PMC 303586 . PMID 3047170. doi:10.1172/JCI113682.
- ^ 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. 2008, 372 (9634): 224–33. PMID 18640459. doi:10.1016/S0140-6736(08)61076-4.
- ^ 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. March 2006, 185 (1): 127–36. PMID 16023124. doi:10.1016/j.atherosclerosis.2005.05.028.
- ^ Franceschini G, Sirtori M, Gianfranceschi G, Sirtori CR. Relation between the HDL apoproteins and A-I isoproteins in subjects with the AIMilano abnormality. Metab. Clin. Exp. May 1981, 30 (5): 502–9. PMID 6785551. doi:10.1016/0026-0495(81)90188-8.
- ^ 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. J. Lipid Res. 2005, 46 (6): 1303–11. PMID 15805548. doi:10.1194/jlr.M400401-JLR200.
- ^ Chiesa G, Sirtori CR. Apolipoprotein A-I(Milano): current perspectives. Curr. Opin. Lipidol. 2003, 14 (2): 159–63. PMID 12642784. doi:10.1097/00041433-200304000-00007.
- ^ 14.0 14.1 Apo A-I-Milano Trial: Where are we now?. Cleveland Clinic. [2008-07-26]. （原始内容存档于2007-12-21）.
- ^ 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. November 2003, 290 (17): 2292–300. PMID 14600188. doi:10.1001/jama.290.17.2292.
- ^ Apo A-I Milano. Cedars-Sinai Heart Institute. [2008-07-26]. （原始内容存档于2007-12-21）.
- ^ 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. Int. J. Cardiol. September 2007, 130 (3): e93–5. PMID 17825930. doi:10.1016/j.ijcard.2007.07.029.
- ^ 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. Diab Vasc Dis Res. June 2007, 4 (2): 124–9. PMID 17654446. doi:10.3132/dvdr.2007.030.
- ^ 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 non-familial AD. Ann. Neurol. 2005, 58 (3): 436–41. PMID 16130094. doi:10.1002/ana.20593.
- ^ Maezawa I, Jin LW, Woltjer RL, Maeda N, Martin GM, Montine TJ, Montine KS. Apolipoprotein E isoforms and apolipoprotein A-I protect from amyloid precursor protein carboxy terminal fragment-associated cytotoxicity. J. Neurochem. 2004, 91 (6): 1312–21. PMID 15584908. doi:10.1111/j.1471-4159.2004.02818.x.
- ^ 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 Rheum. 2006, 54 (11): 3545–50. PMID 17075859. doi:10.1002/art.22201.
- ^ Ma J, Liao XL, Lou B, Wu MP. Role of apolipoprotein A-I in protecting against endotoxin toxicity. Acta Biochim. Biophys. Sin. (Shanghai). 2004, 36 (6): 419–24. PMID 15188057. doi:10.1093/abbs/36.6.419.
- ^ 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. Mol Psychiatry. 2007, 13 (12): 1118–28. PMID 17938634. doi:10.1038/sj.mp.4002108.
- ^ Singh P, Singh M, Kaur T. Role of apolipoproteins E and A-I: Epistatic villains of triglyceride mediation in coronary heart disease. Int J Cardiol. 2008, 134 (3): 410–2. PMID 18378026. doi:10.1016/j.ijcard.2007.12.102.
- ^ 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. Biochim. Biophys. Acta. 2005, 1737 (1): 16–26. PMID 16236546. doi:10.1016/j.bbalip.2005.09.004.
- ^ 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. 2003, 168 (2): 289–95. PMID 12801612. doi:10.1016/S0021-9150(03)00094-7.
- ^ 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. J. Biol. Chem. September 2002, 277 (36): 33178–87. PMID 12084722. doi:10.1074/jbc.M204996200.
- ^ Deeg MA, Bierman EL, Cheung MC. GPI-specific phospholipase D associates with an apoA-I- and apoA-IV-containing complex. J. Lipid Res. March 2001, 42 (3): 442–51. PMID 11254757.
- ^ 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. J. Lipid Res. January 1998, 39 (1): 152–61. PMID 9469594.
- ^ STRING: Known and Predicted Protein-Protein Interactions. （原始内容存档于2011-07-18）.