Heart-type fatty acid binding protein explained

Heart-type fatty acid binding protein (hFABP) also known as mammary-derived growth inhibitor is a protein that in humans is encoded by the FABP3 gene.^{[1] [2]}

Function

Heart-type Fatty Acid-Binding Protein (H-FABP) is a small cytoplasmic protein (15 kDa) released from cardiac myocytes following an ischemic episode.^[3] Like the nine other distinct FABPs that have been identified, H-FABP is involved in active fatty acid metabolism where it transports fatty acids from the cell membrane to mitochondria for oxidation.^[3] See FABP3 for biochemical details.

The intracellular fatty acid-binding proteins (FABPs) belongs to a multigene family. FABPs are divided into at least three distinct types, namely the hepatic-, intestinal- and cardiac-type. They form 14-15 kDa proteins and are thought to participate in the uptake, intracellular metabolism and/or transport of long-chain fatty acids. They may also be responsible in the modulation of cell growth and proliferation. Fatty acid-binding protein 3 gene contains four exons and its function is to arrest growth of mammary epithelial cells. This gene is also a candidate tumor suppressor gene for human breast cancer.^[2]

Interactions

FABP3 is known to interact with TNNI3K in the context of interacting with cardiac troponin I.^[4] The protein also interacts with, VPS28, KIAA159,^[5] NUP62,^[6] PLK1, UBC, and Xpo1.^[2]

In HIV, a synthetic peptide corresponding to the immunosuppressive domain (amino acids 574-592) of HIV-1 gp41 downregulates the expression of fatty acid binding protein 3 (FABP3) in peptide-treated PBMCs.^[7]

Clinical significance

Diagnostic potential

H-FABP is a sensitive biomarker for myocardial infarction^{[8] [9]} and can be detected in the blood within one to three hours of the pain.

The diagnostic potential of the biomarker H-FABP for heart injury was discovered in 1988 by Professor Jan Glatz (Maastricht, Netherlands).^[10] H-FABP is 20 times more specific to cardiac muscle than myoglobin,^[10] it is found at 10-fold lower levels in skeletal muscle than heart muscle and the amounts in the kidney, liver and small intestine are even lower again.^{[11] [12]}

H-FABP is recommended to be measured with troponin to identify myocardial infarction and acute coronary syndrome in patients presenting with chest pain. H-FABP measured with troponin shows increased sensitivity of 20.6% over troponin at 3–6 hours following chest pain onset.^[13] This sensitivity may be explained by the high concentration of H-FABP in myocardium compared to other tissues, the stability and solubility of H-FABP, its low molecular weight; 15kDa compared to 18, 80 and 37kDa for MYO, CK-MB and cTnT respectively,^{[14] [15] [16]} its rapid release into plasma after myocardial injury – 60 minutes after an ischemic episode,^[17] and its relative tissue specificity.^[18] Similarly this study showed that measuring H-FABP in combination with troponin increased the diagnostic accuracy and with a negative predictive value of 98% could be used to identify those not suffering from MI at the early time point of 3–6 hours post chest pain onset.^[13] The effectiveness of using the combination of H-FABP with troponin to diagnose MI within 6 hours is well reported.^{[19] [20] [21]}

Prognostic potential

In addition to its diagnostic potential, H-FABP also has prognostic value. Alongside D-dimer, NT-proBNP and peak troponin T, it was the only cardiac biomarker that proved to be a statistically significant predictor of death or MI at one year. This prognostic information was independent of troponin T, ECG and clinical examination.^[20] The risk associated with raised H-FABP is dependent upon its concentration.^{[22] [23]} Patients who were TnI negative but H-FABP positive had 17% increased risk of all cause mortality within one year compared to those patients who were TnI positive but H-FABP negative.^[22] Currently these TnI positive patients are prioritised for angioplasty, and the TnI negative patients are considered to be of a lower priority, yet the addition of the H-FABP test helps identify patients who are currently slipping through the net and allows physicians to more appropriately manage this hidden high risk group. If both biomarkers were negative, there is 0% mortality at 6 months, in the authors own words this “represents a particularly worthwhile clinical outcome, especially because it was observed in patients admitted into hospital for suspected ACS.” H-FABP indicates risk across the ACS spectrum including UA, NSTEMI or STEMI where low H-FABP concentrations confer low risk whereas high H-FABP concentrations indicate patients who are at a much higher risk of future events.^[22]

H-FABP in other diseases

H-FABP has been proven to significantly predict 30-day mortality in acute pulmonary embolism.^[24] H-FABP is more effective than Troponin T in risk stratifying Chronic Heart Failure patients.^[25] H-FABP is beginning to create interest with researchers who have found emerging evidence that indicates a role in differentiating between different neurodegenerative diseases.^{[26] [27]}

H-FABP Point of care testing

To obtain diagnostic and prognostic information a precise and fully quantitative measurement of H-FABP is required. Commercial tests include a Cardiac Array on Evidence MultiStat; and an automated biochemistry assay

See also

• Akash Manoj – Indian inventor who developed wearable device to detect h-FABP

Further reading

• Spener F, Unterberg C, Börchers T, Grosse R . Characteristics of fatty acid-binding proteins and their relation to mammary-derived growth inhibitor . Molecular and Cellular Biochemistry . 98 . 1–2 . 57–68 . 1991 . 2266970 . 10.1007/bf00231368 . 25352613 .
• Zanotti G, Scapin G, Spadon P, Veerkamp JH, Sacchettini JC . Three-dimensional structure of recombinant human muscle fatty acid-binding protein . The Journal of Biological Chemistry . 267 . 26 . 18541–50 . Sep 1992 . 1526991 . 10.2210/pdb2hmb/pdb.
• Peeters RA, Veerkamp JH, Geurts van Kessel A, Kanda T, Ono T . Cloning of the cDNA encoding human skeletal-muscle fatty-acid-binding protein, its peptide sequence and chromosomal localization . The Biochemical Journal . 276 . Pt 1 . 203–7 . May 1991 . 1710107 . 1151165 . 10.1042/bj2760203.
• Tanaka T, Hirota Y, Sohmiya K, Nishimura S, Kawamura K . Serum and urinary human heart fatty acid-binding protein in acute myocardial infarction . Clinical Biochemistry . 24 . 2 . 195–201 . Apr 1991 . 2040092 . 10.1016/0009-9120(91)90571-U .
• Book: Börchers T, Højrup P, Nielsen SU, Roepstorff P, Spener F, Knudsen J . 1990 . Cellular Fatty Acid-binding Proteins . Revision of the amino acid sequence of human heart fatty acid-binding protein . Molecular and Cellular Biochemistry . 98 . 1–2 . 127–33 . 2266954 . 10.1007/978-1-4615-3936-0_16 . 978-1-4613-6756-7 .
• Offner GD, Brecher P, Sawlivich WB, Costello CE, Troxler RF . Characterization and amino acid sequence of a fatty acid-binding protein from human heart . The Biochemical Journal . 252 . 1 . 191–8 . May 1988 . 3421901 . 1149123 . 10.1042/bj2520191.
• Kovalyov LI, Shishkin SS, Efimochkin AS, Kovalyova MA, Ershova ES, Egorov TA, Musalyamov AK . The major protein expression profile and two-dimensional protein database of human heart . Electrophoresis . 16 . 7 . 1160–9 . Jul 1995 . 7498159 . 10.1002/elps.11501601192 . 32209361 .
• Nielsen SU, Spener F . Fatty acid-binding protein from rat heart is phosphorylated on Tyr19 in response to insulin stimulation . Journal of Lipid Research . 34 . 8 . 1355–66 . Aug 1993 . 10.1016/S0022-2275(20)36965-0 . 7691977 . free .
• Huynh HT, Larsson C, Narod S, Pollak M . Tumor suppressor activity of the gene encoding mammary-derived growth inhibitor . Cancer Research . 55 . 11 . 2225–31 . Jun 1995 . 7757968 .
• Young AC, Scapin G, Kromminga A, Patel SB, Veerkamp JH, Sacchettini JC . Structural studies on human muscle fatty acid binding protein at 1.4 A resolution: binding interactions with three C18 fatty acids . Structure . 2 . 6 . 523–34 . Jun 1994 . 7922029 . 10.1016/S0969-2126(00)00052-6 . free .
• Yang Y, Spitzer E, Kenney N, Zschiesche W, Li M, Kromminga A, Müller T, Spener F, Lezius A, Veerkamp JH . Members of the fatty acid binding protein family are differentiation factors for the mammary gland . The Journal of Cell Biology . 127 . 4 . 1097–109 . Nov 1994 . 7962070 . 2200063 . 10.1083/jcb.127.4.1097 .
• Troxler RF, Offner GD, Jiang JW, Wu BL, Skare JC, Milunsky A, Wyandt HE . Localization of the gene for human heart fatty acid binding protein to chromosome 1p32-1p33 . Human Genetics . 92 . 6 . 563–6 . Dec 1993 . 8262516 . 10.1007/BF00420939 . 11474592 .
• Watanabe K, Wakabayashi H, Veerkamp JH, Ono T, Suzuki T . Immunohistochemical distribution of heart-type fatty acid-binding protein immunoreactivity in normal human tissues and in acute myocardial infarct . The Journal of Pathology . 170 . 1 . 59–65 . May 1993 . 8326460 . 10.1002/path.1711700110 . 20506087 .
• Zhao Y, Meng XM, Wei YJ, Zhao XW, Liu DQ, Cao HQ, Liew CC, Ding JF . Cloning and characterization of a novel cardiac-specific kinase that interacts specifically with cardiac troponin I . Journal of Molecular Medicine . 81 . 5 . 297–304 . May 2003 . 12721663 . 10.1007/s00109-003-0427-x . 13468188 .
• Book: Cheon MS, Kim SH, Fountoulakis M, Lubec G . Advances in Down Syndrome Research . Heart type fatty acid binding protein (H-FABP) is decreased in brains of patients with Down syndrome and Alzheimer's disease . Journal of Neural Transmission. Supplementum . 67. 67 . 225–34 . 15068254 . 10.1007/978-3-7091-6721-2_20 . Journal of Neural Transmission Supplement 67 . 2003 . 978-3-211-40776-9 .
• Hashimoto T, Kusakabe T, Sugino T, Fukuda T, Watanabe K, Sato Y, Nashimoto A, Honma K, Kimura H, Fujii H, Suzuki T . Expression of heart-type fatty acid-binding protein in human gastric carcinoma and its association with tumor aggressiveness, metastasis and poor prognosis . Pathobiology . 71 . 5 . 267–73 . 2005 . 15459486 . 10.1159/000080061 . 983644 .

Notes and References

1. Phelan CM, Larsson C, Baird S, Futreal PA, Ruttledge MH, Morgan K, Tonin P, Hung H, Korneluk RG, Pollak MN, Narod SA . The human mammary-derived growth inhibitor (MDGI) gene: genomic structure and mutation analysis in human breast tumors . Genomics . 34 . 1 . 63–8 . May 1996 . 8661024 . 10.1006/geno.1996.0241 . 22867711 .
2. Web site: Entrez Gene: FABP3 fatty acid binding protein 3, muscle and heart (mammary-derived growth inhibitor).
3. Kleine AH, Glatz JF, Van Nieuwenhoven FA, Van der Vusse GJ . Release of heart fatty acid-binding protein into plasma after acute myocardial infarction in man . Molecular and Cellular Biochemistry . 116 . 1–2 . 155–62 . Oct 1992 . 1480144 . 10.1007/BF01270583 . 12883346 .
4. Zhao Y, Meng XM, Wei YJ, Zhao XW, Liu DQ, Cao HQ, Liew CC, Ding JF . Cloning and characterization of a novel cardiac-specific kinase that interacts specifically with cardiac troponin I . Journal of Molecular Medicine . 81 . 5 . 297–304 . May 2003 . 12721663 . 10.1007/s00109-003-0427-x . 13468188 .
5. Stelzl U, Worm U, Lalowski M, Haenig C, Brembeck FH, Goehler H, Stroedicke M, Zenkner M, Schoenherr A, Koeppen S, Timm J, Mintzlaff S, Abraham C, Bock N, Kietzmann S, Goedde A, Toksöz E, Droege A, Krobitsch S, Korn B, Birchmeier W, Lehrach H, Wanker EE . A human protein-protein interaction network: a resource for annotating the proteome . Cell . 122 . 6 . 957–68 . Sep 2005 . 16169070 . 10.1016/j.cell.2005.08.029 . 11858/00-001M-0000-0010-8592-0 . 8235923 . free .
6. Svendsen JM, Smogorzewska A, Sowa ME, O'Connell BC, Gygi SP, Elledge SJ, Harper JW . Mammalian BTBD12/SLX4 assembles a Holliday junction resolvase and is required for DNA repair . Cell . 138 . 1 . 63–77 . Jul 2009 . 19596235 . 10.1016/j.cell.2009.06.030 . 2720686.
7. Denner J, Eschricht M, Lauck M, Semaan M, Schlaermann P, Ryu H, Akyüz L . Modulation of cytokine release and gene expression by the immunosuppressive domain of gp41 of HIV-1 . PLOS ONE . 8 . 1 . e55199 . 2013 . 23383108 . 10.1371/journal.pone.0055199 . 3559347. 2013PLoSO...855199D . free .
8. Tanaka T, Hirota Y, Sohmiya K, Nishimura S, Kawamura K . Serum and urinary human heart fatty acid-binding protein in acute myocardial infarction . Clinical Biochemistry . 24 . 2 . 195–201 . Apr 1991 . 2040092 . 10.1016/0009-9120(91)90571-U .
9. Watanabe K, Wakabayashi H, Veerkamp JH, Ono T, Suzuki T . Immunohistochemical distribution of heart-type fatty acid-binding protein immunoreactivity in normal human tissues and in acute myocardial infarct . The Journal of Pathology . 170 . 1 . 59–65 . May 1993 . 8326460 . 10.1002/path.1711700110 . 20506087 .
10. Glatz JF, van Bilsen M, Paulussen RJ, Veerkamp JH, van der Vusse GJ, Reneman RS . Release of fatty acid-binding protein from isolated rat heart subjected to ischemia and reperfusion or to the calcium paradox . Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism . 961 . 1 . 148–52 . Jul 1988 . 3260112 . 10.1016/0005-2760(88)90141-5 .
11. Ghani F, Wu AH, Graff L, Petry C, Armstrong G, Prigent F, Brown M . Role of heart-type fatty acid-binding protein in early detection of acute myocardial infarction . Clinical Chemistry . 46 . 5 . 718–9 . May 2000 . 10794758 . 10.1093/clinchem/46.5.718. free .
12. Pelsers MM, Hermens WT, Glatz JF . Fatty acid-binding proteins as plasma markers of tissue injury . Clinica Chimica Acta; International Journal of Clinical Chemistry . 352 . 1–2 . 15–35 . Feb 2005 . 15653098 . 10.1016/j.cccn.2004.09.001 .
13. McMahon G, Lamont J, Curtin E, McConnell RI, Crockard M, Kurth MJ, Crean P, Fitzgerald SP . Diagnostic accuracy of H-FABP for the early diagnosis of acute myocardial infarction . American Journal of Emergency Medicine. 2011 . in press.
14. Glatz JF, Kleine AH, van Nieuwenhoven FA, Hermens WT, van Dieijen-Visser MP, van der Vusse GJ . Fatty-acid-binding protein as a plasma marker for the estimation of myocardial infarct size in humans . British Heart Journal . 71 . 2 . 135–40 . Feb 1994 . 8130020 . 483632 . 10.1136/hrt.71.2.135 .
15. Wodzig KW, Kragten JA, Hermens WT, Glatz JF, van Dieijen-Visser MP . Estimation of myocardial infarct size from plasma myoglobin or fatty acid-binding protein. Influence of renal function . European Journal of Clinical Chemistry and Clinical Biochemistry . 35 . 3 . 191–8 . Mar 1997 . 9127740 . 10.1515/cclm.1997.35.3.191 . 10.1.1.634.2919 . 33514349 .
16. Michielsen EC, Diris JH, Kleijnen VW, Wodzig WK, Van Dieijen-Visser MP . Interpretation of cardiac troponin T behaviour in size-exclusion chromatography . Clinical Chemistry and Laboratory Medicine . 44 . 12 . 1422–7 . 2006 . 17163817 . 10.1515/CCLM.2006.265 . 10595147 .
17. Van Nieuwenhoven FA, Kleine AH, Wodzig WH, Hermens WT, Kragten HA, Maessen JG, Punt CD, Van Dieijen MP, Van der Vusse GJ, Glatz JF . Discrimination between myocardial and skeletal muscle injury by assessment of the plasma ratio of myoglobin over fatty acid-binding protein . Circulation . 92 . 10 . 2848–54 . Nov 1995 . 7586251 . 10.1161/01.cir.92.10.2848 .
18. Alhadi HA, Fox KA . Do we need additional markers of myocyte necrosis: the potential value of heart fatty-acid-binding protein . QJM . 97 . 4 . 187–98 . Apr 2004 . 15028848 . 10.1093/qjmed/hch037 . free .
19. Azzazy HM, Pelsers MM, Christenson RH . Unbound free fatty acids and heart-type fatty acid-binding protein: diagnostic assays and clinical applications . Clinical Chemistry . 52 . 1 . 19–29 . Jan 2006 . 16269514 . 10.1373/clinchem.2005.056143 . free .
20. McCann CJ, Glover BM, Menown IB, Moore MJ, McEneny J, Owens CG, Smith B, Sharpe PC, Young IS, Adgey JA . Novel biomarkers in early diagnosis of acute myocardial infarction compared with cardiac troponin T . European Heart Journal . 29 . 23 . 2843–50 . Dec 2008 . 18682444 . 10.1093/eurheartj/ehn363 . free .
21. Li CJ, Li JQ, Liang XF, Li XX, Cui JG, Yang ZJ, Guo Q, Cao KJ, Huang J . Point-of-care test of heart-type fatty acid-binding protein for the diagnosis of early acute myocardial infarction . Acta Pharmacologica Sinica . 31 . 3 . 307–12 . Mar 2010 . 20140003 . 4002415 . 10.1038/aps.2010.2 .
22. Kilcullen N, Viswanathan K, Das R, Morrell C, Farrin A, Barth JH, Hall AS . Heart-type fatty acid-binding protein predicts long-term mortality after acute coronary syndrome and identifies high-risk patients across the range of troponin values . Journal of the American College of Cardiology . 50 . 21 . 2061–7 . Nov 2007 . 18021874 . 10.1016/j.jacc.2007.08.021 . free .
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27. Lescuyer P, Allard L, Zimmermann-Ivol CG, Burgess JA, Hughes-Frutiger S, Burkhard PR, Sanchez JC, Hochstrasser DF . Identification of post-mortem cerebrospinal fluid proteins as potential biomarkers of ischemia and neurodegeneration . Proteomics . 4 . 8 . 2234–41 . Aug 2004 . 15274117 . 10.1002/pmic.200300822 . 46117550 .