Fatty acid-binding protein 4 (FABP4): Pathophysiological insights and potent clinical biomarker of metabolic and cardiovascular diseases

Clinical Medicine Insights: Cardiology

Volumn 2014, Issue , 2014, Pages 23-33

  Furuhashi, Masato ^a   Saitoh, Shigeyuki ^b   Shimamoto, Kazuaki ^b   Miura, Tetsuji ^a  

^a SAPPORO MEDICAL UNIVERSITY SCHOOL OF MEDICINE   (Japan)

^b SAPPORO MEDICAL UNIVERSITY   (Japan)

Author keywords

Cardiovascular disease; Fatty acid binding protein; Inflammation; Metabolic syndrome

Indexed keywords

FATTY ACID BINDING PROTEIN; FATTY ACID BINDING PROTEIN 4; FATTY ACID BINDING PROTEIN 5; UNCLASSIFIED DRUG;

ADIPOCYTE; ATHEROSCLEROSIS; DISEASE ASSOCIATION; HUMAN; HYPERTENSION; IN VITRO STUDY; IN VIVO STUDY; INSULIN RESISTANCE; LEFT VENTRICULAR DIASTOLIC DYSFUNCTION; LIPOGENESIS; MACROPHAGE; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; NUCLEAR LOCALIZATION SIGNAL; OBESITY; PATHOPHYSIOLOGY; PROSPECTIVE STUDY; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN SECRETION; PROTEOMICS; REVIEW;

EID: 84981738067     PISSN: None     EISSN: 11795468     Source Type: Journal    
DOI: 10.4137/CMC.S17067     Document Type: Review

References (152)

1. Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006;444(7121):860–7.
2. Gregor MF, Hotamisligil GS. Inflammatory mechanisms in obesity. Annu Rev Immunol. 2011;29:415–45.
3. Hirosumi J, Tuncman G, Chang L, et al. A central role for JNK in obesity and insulin resistance. Nature. 2002;420(6913):333–6.
4. Yuan M, Konstantopoulos N, Lee J, et al. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science. 2001;293(5535):1673–7.
5. Nakamura T, Furuhashi M, Li P, et al. Double-stranded RNA-dependent protein kinase links pathogen sensing with stress and metabolic homeostasis. Cell. 2010;140(3):338–48.
6. Furuhashi M, Hotamisligil GS. Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets. Nat Rev Drug Discov. 2008;7(6):489–503.
7. Furuhashi M, Ishimura S, Ota H, Miura T. Lipid chaperones and metabolic inflammation. Int J Inflam. 2011;2011:642612.
8. Coe NR, Bernlohr DA. Physiological properties and functions of intracellular fatty acid-binding proteins. Biochim Biophys Acta. 1998;1391(3):287–306.
9. Zimmerman AW, Veerkamp JH. New insights into the structure and function of fatty acid-binding proteins. Cell Mol Life Sci. 2002;59(7):1096–116.
10. Haunerland NH, Spener F. Fatty acid-binding proteins – insights from genetic manipulations. Prog Lipid Res. 2004;43(4):328–49.
11. Chmurzynska A. The multigene family of fatty acid-binding proteins (FABPs): function, structure and polymorphism. J Appl Genet. 2006;47(1):39–48.
12. Esteves A, Ehrlich R. Invertebrate intracellular fatty acid binding proteins. Comp Biochem Physiol C Toxicol Pharmacol. 2006;142(3–4):262–74.
13. Ockner RK, Manning JA, Poppenhausen RB, Ho WK. A binding protein for fatty acids in cytosol of intestinal mucosa, liver, myocardium, and other tissues. Science. 1972;177(4043):56–8.
14. Veerkamp JH, van Moerkerk HT. Fatty acid-binding protein and its relation to fatty acid oxidation. Mol Cell Biochem. 1993;123(1–2):101–6.
15. Ek BA, Cistola DP, Hamilton JA, Kaduce TL, Spector AA. Fatty acid binding proteins reduce 15-lipoxygenase-induced oxygenation of linoleic acid and arachidonic acid. Biochim Biophys Acta. 1997;1346(1):75–85.
16. Zimmer JS, Dyckes DF, Bernlohr DA, Murphy RC. Fatty acid binding proteins stabilize leukotriene A4: competition with arachidonic acid but not other lipoxygenase products. J Lipid Res. 2004;45(11):2138–44.
17. Spiegelman BM, Frank M, Green H. Molecular cloning of mRNA from 3T3 adipocytes. Regulation of mRNA content for glycerophosphate dehydrogenase and other differentiation-dependent proteins during adipocyte development. J Biol Chem. 1983;258(16):10083–9.
18. Hunt CR, Ro JH, Dobson DE, Min HY, Spiegelman BM. Adipocyte P2 gene: developmental expression and homology of 5’-flanking sequences among fat cell-specific genes. Proc Natl Acad Sci U S A. 1986;83(11):3786–90.
19. Baxa CA, Sha RS, Buelt MK, et al. Human adipocyte lipid-binding protein: purification of the protein and cloning of its complementary DNA. Biochemistry. 1989;28(22):8683–90.
20. Amri EZ, Bertrand B, Ailhaud G, Grimaldi P. Regulation of adipose cell differentiation. I. Fatty acids are inducers of the aP2 gene expression. J Lipid Res. 1991;32(9):1449–56.
21. Distel RJ, Robinson GS, Spiegelman BM. Fatty acid regulation of gene expression. Transcriptional and post-transcriptional mechanisms. J Biol Chem. 1992;267(9):5937–41.
22. Kletzien RF, Foellmi LA, Harris PK, Wyse BM, Clarke SD. Adipocyte fatty acid-binding protein: regulation of gene expression in vivo and in vitro by an insulin-sensitizing agent. Mol Pharmacol. 1992;42(4):558–62.
23. Cook JS, Lucas JJ, Sibley E, et al. Expression of the differentiation-induced gene for fatty acid-binding protein is activated by glucocorticoid and cAMP. Proc Natl Acad Sci U S A. 1988;85(9):2949–53.
24. Melki SA, Abumrad NA. Expression of the adipocyte fatty acid-binding protein in streptozotocin-diabetes: effects of insulin deficiency and supplementation. J Lipid Res. 1993;34(9):1527–34.
25. Hotamisligil GS, Johnson RS, Distel RJ, Ellis R, Papaioannou VE, Spiegelman BM. Uncoupling of obesity from insulin resistance through a targeted mutation in aP2, the adipocyte fatty acid binding protein. Science. 1996;274(5291):1377–9.
26. Uysal KT, Scheja L, Wiesbrock SM, Bonner-Weir S, Hotamisligil GS. Improved glucose and lipid metabolism in genetically obese mice lacking aP2. Endocrinology. 2000;141(9):3388–96.
27. Shen WJ, Sridhar K, Bernlohr DA, Kraemer FB. Interaction of rat hormone-sensitive lipase with adipocyte lipid-binding protein. Proc Natl Acad Sci U S A. 1999;96(10):5528–32.
28. Smith AJ, Sanders MA, Juhlmann BE, Hertzel AV, Bernlohr DA. Mapping of the hormone-sensitive lipase binding site on the adipocyte fatty acid-binding protein (AFABP). Identification of the charge quartet on the AFABP/aP2 helix-turn-helix domain. J Biol Chem. 2008;283(48):33536–43.
29. Scheja L, Makowski L, Uysal KT, et al. Altered insulin secretion associated with reduced lipolytic efficiency in aP2-/-mice. Diabetes. 1999;48(10):1987–94.
30. Coe NR, Simpson MA, Bernlohr DA. Targeted disruption of the adipocyte lipid-binding protein (aP2 protein) gene impairs fat cell lipolysis and increases cellular fatty acid levels. J Lipid Res. 1999;40(5):967–72.
31. Yang R, Castriota G, Chen Y, et al. RNAi-mediated germline knockdown of FABP4 increases body weight but does not improve the deranged nutrient metabolism of diet-induced obese mice. Int J Obes. 2011;35(2):217–25.
32. Simpson MA, LiCata VJ, Ribarik Coe N, Bernlohr DA. Biochemical and biophysical analysis of the intracellular lipid binding proteins of adipocytes. Mol Cell Biochem. 1999;192(1–2):33–40.
33. Maeda K, Uysal KT, Makowski L, et al. Role of the fatty acid binding protein mal1 in obesity and insulin resistance. Diabetes. 2003;52(2):300–7.
34. Hertzel AV, Bennaars-Eiden A, Bernlohr DA. Increased lipolysis in transgenic animals overexpressing the epithelial fatty acid binding protein in adipose cells. J Lipid Res. 2002;43(12):2105–11.
35. Owada Y, Suzuki I, Noda T, Kondo H. Analysis on the phenotype of E-FABP-gene knockout mice. Mol Cell Biochem. 2002;239(1–2):83–6.
36. Makowski L, Boord JB, Maeda K, et al. Lack of macrophage fatty-acid-binding protein aP2 protects mice deficient in apolipoprotein E against atherosclerosis. Nat Med. 2001;7(6):699–705.
37. Rolph MS, Young TR, Shum BO, et al. Regulation of dendritic cell function and T cell priming by the fatty acid-binding protein AP2. J Immunol. 2006;177(11):7794–801.
38. Shum BO, Mackay CR, Gorgun CZ, et al. The adipocyte fatty acid-binding protein aP2 is required in allergic airway inflammation. J Clin Invest. 2006;116(8):2183–92.
39. Fu Y, Luo N, Lopes-Virella MF, Garvey WT. The adipocyte lipid binding protein (ALBP/aP2) gene facilitates foam cell formation in human THP-1 macrophages. Atherosclerosis. 2002;165(2):259–69.
40. Kazemi MR, McDonald CM, Shigenaga JK, Grunfeld C, Feingold KR. Adipocyte fatty acid-binding protein expression and lipid accumulation are increased during activation of murine macrophages by toll-like receptor agonists. Arterioscler Thromb Vasc Biol. 2005;25(6):1220–4.
41. Pelton PD, Zhou L, Demarest KT, Burris TP. PPARgamma activation induces the expression of the adipocyte fatty acid binding protein gene in human monocytes. Biochem Biophys Res Commun. 1999;261(2):456–8.
42. Fu Y, Luo N, Lopes-Virella MF. Oxidized LDL induces the expression of ALBP/aP2 mRNA and protein in human THP-1 macrophages. J Lipid Res. 2000;41(12):2017–23.
43. Wang XQ, Yang K, He YS, Lu L, Shen WF. Receptor mediated elevation in FABP4 levels by advanced glycation end products induces cholesterol and triacylglycerol accumulation in THP-1 macrophages. Lipids. 2011;46(6):479–86.
44. Llaverias G, Noé V, Peñuelas S, et al. Atorvastatin reduces CD68, FABP4, and HBP expression in oxLDL-treated human macrophages. Biochem Biophys Res Commun. 2004;318(1):265–74.
45. Song J, Ren P, Zhang L, Wang XL, Chen L, Shen YH. Metformin reduces lipid accumulation in macrophages by inhibiting FOXO1-mediated transcription of fatty acid-binding protein 4. Biochem Biophys Res Commun. 2010;393(1):89–94.
46. Makowski L, Brittingham KC, Reynolds JM, Suttles J, Hotamisligil GS. The fatty acid-binding protein, aP2, coordinates macrophage cholesterol trafficking and inflammatory activity. Macrophage expression of aP2 impacts peroxisome proliferator-activated receptor gamma and IkappaB kinase activities. J Biol Chem. 2005;280(13):12888–95.
47. Hui X, Li H, Zhou Z, et al. Adipocyte fatty acid-binding protein modulates inflammatory responses in macrophages through a positive feedback loop involving c-Jun NH2-terminal kinases and activator protein−1. J Biol Chem. 2010;285(14):10273–80.
48. Boord JB, Maeda K, Makowski L, et al. Adipocyte fatty acid-binding protein, aP2, alters late atherosclerotic lesion formation in severe hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2002;22(10):1686–91.
49. Hansson GK, Hermansson A. The immune system in atherosclerosis. Nat Immunol. 2011;12(3):204–12.
50. Agardh HE, Folkersen L, Ekstrand J, et al. Expression of fatty acid-binding protein 4/aP2 is correlated with plaque instability in carotid atherosclerosis. J Intern Med. 2011;269(2):200–10.
51. Feingold KR, Kazemi MR, Magra AL, et al. ADRP/ADFP and Mal1 expression are increased in macrophages treated with TLR agonists. Atherosclerosis. 2010;209(1):81–8.
52. Babaev VR, Runner RP, Fan D, et al. Macrophage Mal1 deficiency suppresses atherosclerosis in low-density lipoprotein receptor-null mice by activating peroxisome proliferator-activated receptor-gamma-regulated genes. Arterioscler Thromb Vasc Biol. 2011;31(6):1283–90.
53. Maeda K, Cao H, Kono K, et al. Adipocyte/macrophage fatty acid binding proteins control integrated metabolic responses in obesity and diabetes. Cell Metab. 2005;1(2):107–19.
54. Cao H, Maeda K, Gorgun CZ, et al. Regulation of metabolic responses by adipocyte/macrophage fatty acid-binding proteins in leptin-deficient mice. Diabetes. 2006;55(7):1915–22.
55. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112(12):1796–808.
56. Xu H, Barnes GT, Yang Q, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003;112(12):1821–30.
57. Furuhashi M, Fucho R, Gorgun CZ, Tuncman G, Cao H, Hotamisligil GS. Adipocyte/macrophage fatty acid-binding proteins contribute to metabolic deterioration through actions in both macrophages and adipocytes in mice. J Clin Invest. 2008;118(7):2640–50.
58. Boord JB, Maeda K, Makowski L, et al. Combined adipocyte-macrophage fatty acid-binding protein deficiency improves metabolism, atherosclerosis, and survival in apolipoprotein E-deficient mice. Circulation. 2004;110(11):1492–8.
59. Cao H, Gerhold K, Mayers JR, Wiest MM, Watkins SM, Hotamisligil GS. Identification of a lipokine, a lipid hormone linking adipose tissue to systemic metabolism. Cell. 2008;134(6):933–44.
60. Erbay E, Babaev VR, Mayers JR, et al. Reducing endoplasmic reticulum stress through a macrophage lipid chaperone alleviates atherosclerosis. Nat Med. 2009;15(12):1383–91.
61. Coleman SL, Park YK, Lee JY. Unsaturated fatty acids repress the expression of adipocyte fatty acid binding protein via the modulation of histone deacetylation in RAW 264.7 macrophages. Eur J Nutr. 2011;50(5):323–30.
62. Stefan N, Kantartzis K, Celebi N, et al. Circulating palmitoleate strongly and independently predicts insulin sensitivity in humans. Diabetes Care. 2010;33(2):405–7.
63. Mozaffarian D, Cao H, King IB, et al. Circulating palmitoleic acid and risk of metabolic abnormalities and new-onset diabetes. Am J Clin Nutr. 2010;92(6):1350–8.
64. Mozaffarian D, Cao H, King IB, et al. Trans-palmitoleic acid, metabolic risk factors, and new-onset diabetes in U.S. adults: a cohort study. Ann Intern Med. 2010;153(12):790–9.
65. Ayers SD, Nedrow KL, Gillilan RE, Noy N. Continuous nucleocytoplasmic shuttling underlies transcriptional activation of PPARgamma by FABP4. Biochemistry. 2007;46(23):6744–52.
66. Gillilan RE, Ayers SD, Noy N. Structural basis for activation of fatty acid-binding protein 4. J Mol Biol. 2007;372(5):1246–60.
67. Tan NS, Shaw NS, Vinckenbosch N, et al. Selective cooperation between fatty acid binding proteins and peroxisome proliferator-activated receptors in regulating transcription. Mol Cell Biol. 2002;22(14):5114–27.
68. Thompson BR, Mazurkiewicz-Munoz AM, Suttles J, Carter-Su C, Bernlohr DA. Interaction of adipocyte fatty acid-binding protein (AFABP) and JAK2: AFABP/aP2 as a regulator of JAK2 signaling. J Biol Chem. 2009;284(20):13473–80.
69. Gorbenko O, Panayotou G, Zhyvoloup A, Volkova D, Gout I, Filonenko V. Identification of novel PTEN-binding partners: PTEN interaction with fatty acid binding protein FABP4. Mol Cell Biochem. 2010;337(1–2):299–305.
70. Tsuda M, Inoue-Narita T, Suzuki A, Itami S, Blumenberg M, Manabe M. Induction of gene encoding FABP4 in Pten-null keratinocytes. FEBS Lett. 2009;583(8):1319–22.
71. Nickel W, Rabouille C. Mechanisms of regulated unconventional protein secretion. Nat Rev Mol Cell Biol. 2009;10(2):148–55.
72. Cao H, Sekiya M, Ertunc ME, et al. Adipocyte lipid chaperone AP2 is a secreted adipokine regulating hepatic glucose production. Cell Metab. 2013;17(5):768–78.
73. Kralisch S, Ebert T, Lossner U, Jessnitzer B, Stumvoll M, Fasshauer M. Adipocyte fatty acid-binding protein is released from adipocytes by a non-conventional mechanism. Int J Obes (Lond). 2014;38(9):1251–4.
74. Stich V, Berlan M. Physiological regulation of NEFA availability: lipolysis pathway. Proc Nutr Soc. 2004;63(2):369–74.
75. Moro C, Lafontan M. Natriuretic peptides and cGMP signaling control of energy homeostasis. Am J Physiol Heart Circ Physiol. 2013;304(3):H358–68.
76. Mita T, Furuhashi M, Hiramitsu S, et al. FABP4 is secreted from adipocytes by adenyl cyclase-PKA- and guanylyl cyclase-PKG-dependent lipolytic mechanisms. Obesity (Silver Spring). December 17, 2014. doi: 10.1002/oby.20954. [Epub ahead of print]
77. Schlottmann I, Ehrhart-Bornstein M, Wabitsch M, Bornstein SR, Lamounier-Zepter V. Calcium-dependent release of adipocyte fatty acid binding protein from human adipocytes. Int J Obes (Lond). 2014;38(9):1221–7.
78. Lamounier-Zepter V, Look C, Alvarez J, et al. Adipocyte fatty acid-binding protein suppresses cardiomyocyte contraction: a new link between obesity and heart disease. Circ Res. 2009;105(4):326–34.
79. Fach EM, Garulacan LA, Gao J, et al. In vitro biomarker discovery for atherosclerosis by proteomics. Mol Cell Proteomics. 2004;3(12):1200–10.
80. Aragones G, Saavedra P, Heras M, Cabre A, Girona J, Masana L. Fatty acid-binding protein 4 impairs the insulin-dependent nitric oxide pathway in vascular endothelial cells. Cardiovasc Diabetol. 2012;11(1):72.
81. Girona J, Rosales R, Plana N, Saavedra P, Masana L, Vallve JC. FABP4 induces vascular smooth muscle cell proliferation and migration through a MAPK-dependent pathway. PLoS One. 2013;8(11):e81914.
82. Wu LE, Samocha-Bonet D, Whitworth PT, et al. Identification of fatty acid binding protein 4 as an adipokine that regulates insulin secretion during obesity. Mol Metab. 2014;3(4):465–73.
83. Pelsers MM, Hermens WT, Glatz JF. Fatty acid-binding proteins as plasma markers of tissue injury. Clin Chim Acta. 2005;352(1–2):15–35.
84. Pelsers MM, Morovat A, Alexander GJ, Hermens WT, Trull AK, Glatz JF. Liver fatty acid-binding protein as a sensitive serum marker of acute hepatocellular damage in liver transplant recipients. Clin Chem. 2002;48(11):2055–7.
85. Pelsers MM, Namiot Z, Kisielewski W, et al. Intestinal-type and liver-type fatty acid-binding protein in the intestine. Tissue distribution and clinical utility. Clin Biochem. 2003;36(7):529–35.
86. Tanaka T, Hirota Y, Sohmiya K, Nishimura S, Kawamura K. Serum and urinary human heart fatty acid-binding protein in acute myocardial infarction. Clin Biochem. 1991;24(2):195–201.
87. Setsuta K, Seino Y, Ogawa T, Arao M, Miyatake Y, Takano T. Use of cytosolic and myofibril markers in the detection of ongoing myocardial damage in patients with chronic heart failure. Am J Med. 2002;113(9):717–22.
88. Pelsers MM, Hanhoff T, Van der Voort D, et al. Brain- and heart-type fatty acid-binding proteins in the brain: tissue distribution and clinical utility. Clin Chem. 2004;50(9):1568–75.
89. Ishimura S, Furuhashi M, Watanabe Y, et al. Circulating levels of fatty acid-binding protein family and metabolic phenotype in the general population. PLoS One. 2013;8(11):e81318.
90. Xu A, Wang Y, Xu JY, et al. Adipocyte fatty acid-binding protein is a plasma biomarker closely associated with obesity and metabolic syndrome. Clin Chem. 2006;52(3):405–13.
91. Furuhashi M, Ura N, Hasegawa K, et al. Serum ratio of heart-type fatty acid-binding protein to myoglobin. A novel marker of cardiac damage and volume overload in hemodialysis patients. Nephron Clin Pract. 2003;93(2):C69–74.
92. Furuhashi M, Ura N, Hasegawa K, Tsuchihashi K, Nakata T, Shimamoto K. Utility of serum ratio of heart-type fatty acid-binding protein to myoglobin for cardiac damage regardless of renal dysfunction. Circ J. 2004;68(7):656–9.
93. Yeung DC, Xu A, Tso AW, et al. Circulating levels of adipocyte and epidermal fatty acid-binding proteins in relation to nephropathy staging and macrovascular complications in type 2 diabetic patients. Diabetes Care. 2009;32(1):132–4.
94. Furuhashi M, Ishimura S, Ota H, et al. Serum fatty acid-binding protein 4 is a predictor of cardiovascular events in end-stage renal disease. PLoS One. 2011;6(11):e27356.
95. Xu A, Tso AW, Cheung BM, et al. Circulating adipocyte-fatty acid binding protein levels predict the development of the metabolic syndrome: a 5-year prospective study. Circulation. 2007;115(12):1537–43.
96. Tso AW, Xu A, Sham PC, et al. Serum adipocyte fatty acid binding protein as a new biomarker predicting the development of type 2 diabetes: a 10-year prospective study in a Chinese cohort. Diabetes Care. 2007;30(10):2667–72.
97. Ota H, Furuhashi M, Ishimura S, et al. Elevation of fatty acid-binding protein 4 is predisposed by family history of hypertension and contributes to blood pressure elevation. Am J Hypertens. 2012;25(10):1124–30.
98. Fuseya T, Furuhashi M, Yuda S, et al. Elevation of circulating fatty acid-binding protein 4 is independently associated with left ventricular diastolic dysfunction in a general population. Cardiovasc Diabetol. 2014;13(1):126.
99. Yeung DC, Xu A, Cheung CW, et al. Serum adipocyte fatty acid-binding protein levels were independently associated with carotid atherosclerosis. Arterioscler Thromb Vasc Biol. 2007;27(8):1796–802.
100. Balci MM, Arslan U, Firat H, et al. Serum levels of adipocyte fatty acid-binding protein are independently associated with left ventricular mass and myocardial performance index in obstructive sleep apnea syndrome. J Investig Med. 2012;60(7):1020–6.
101. Engeli S, Utz W, Haufe S, et al. Fatty acid binding protein 4 predicts left ventricular mass and longitudinal function in overweight and obese women. Heart. 2013;99(13):944–8.
102. Huang CL, Wu YW, Wu CC, et al. Association between serum adipocyte fatty-acid binding protein concentrations, left ventricular function and myocardial perfusion abnormalities in patients with coronary artery disease. Cardiovasc Diabetol. 2013;12:105.
103. Liu M, Zhou M, Bao Y, et al. Circulating adipocyte fatty acid-binding protein levels are independently associated with heart failure. Clin Sci. 2013;124(2):115–22.
104. Baessler A, Lamounier-Zepter V, Fenk S, et al. Adipocyte fatty acid-binding protein levels are associated with left ventricular diastolic dysfunction in morbidly obese subjects. Nutr Diabetes. 2014;4:e106.
105. Tuncman G, Erbay E, Hom X, et al. A genetic variant at the fatty acid-binding protein aP2 locus reduces the risk for hypertriglyceridemia, type 2 diabetes, and cardiovascular disease. Proc Natl Acad Sci U S A. 2006;103(18):6970–5.
106. von Eynatten M, Breitling LP, Roos M, Baumann M, Rothenbacher D, Brenner H. Circulating adipocyte fatty acid-binding protein levels and cardiovascular morbidity and mortality in patients with coronary heart disease: a 10-year prospective study. Arterioscler Thromb Vasc Biol. 2012;32(9):2327–35.
107. Chow WS, Tso AW, Xu A, et al. Elevated circulating adipocyte-fatty acid binding protein levels predict incident cardiovascular events in a community-based cohort: a 12-year prospective study. J Am Heart Assoc. 2013;2(1):e004176.
108. Djoussé L, Bartz TM, Ix JH, et al. Fatty acid-binding protein 4 and incident heart failure: the cardiovascular health study. Eur J Heart Fail. 2013;15(4):394–9.
109. Hancke K, Grubeck D, Hauser N, Kreienberg R, Weiss JM. Adipocyte fatty acid-binding protein as a novel prognostic factor in obese breast cancer patients. Breast Cancer Res Treat. 2010;119(2):367–7.
110. Karpisek M, Stejskal D, Kotolova H, et al. Treatment with atorvastatin reduces serum adipocyte-fatty acid binding protein value in patients with hyperlipidaemia. Eur J Clin Invest. 2007;37(8):637–42.
111. Miyoshi T, Doi M, Hirohata S, et al. Olmesartan reduces arterial stiffness and serum adipocyte fatty acid-binding protein in hypertensive patients. Heart Vessels. 2011;26(4):408–13.
112. Furuhashi M, Mita T, Moniwa N, et al. Angiotensin II receptor blockers decrease serum concentration of fatty acid-binding protein 4 in patients with hypertension. Hypertens Res. 2015;(In press).
113. Cabré A, Lázaro I, Girona J, et al. Fatty acid binding protein 4 is increased in metabolic syndrome and with thiazolidinedione treatment in diabetic patients. Atherosclerosis. 2007;195(1):e150–8.
114. Schachtrup C, Emmler T, Bleck B, Sandqvist A, Spener F. Functional analysis of peroxisome-proliferator-responsive element motifs in genes of fatty acid-binding proteins. Biochem J. 2004;382(pt 1):239–45.
115. Yeung DC, Wang Y, Xu A, et al. Epidermal fatty-acid-binding protein: a new circulating biomarker associated with cardio-metabolic risk factors and carotid atherosclerosis. Eur Heart J. 2008;29(17):2156–63.
116. Bagheri R, Qasim AN, Mehta NN, et al. Relation of plasma fatty acid binding proteins 4 and 5 with the metabolic syndrome, inflammation and coronary calcium in patients with type-2 diabetes mellitus. Am J Cardiol. 2010;106(8):1118–23.
117. Elmasri H, Karaaslan C, Teper Y, et al. Fatty acid binding protein 4 is a target of VEGF and a regulator of cell proliferation in endothelial cells. FASEB J. 2009;23(11):3865–73.
118. Iso T, Maeda K, Hanaoka H, et al. Capillary endothelial fatty acid binding proteins 4 and 5 play a critical role in fatty acid uptake in heart and skeletal muscle. Arterioscler Thromb Vasc Biol. 2013;33(11):2549–57.
119. Elmasri H, Ghelfi E, Yu CW, et al. Endothelial cell-fatty acid binding protein 4 promotes angiogenesis: role of stem cell factor/c-kit pathway. Angiogenesis. 2012;15(3):457–68.
120. Saint-Geniez M, Ghelfi E, Liang X, et al. Fatty acid binding protein 4 deficiency protects against oxygen-induced retinopathy in mice. PLoS One. 2014;9(5):e96253.
121. Harjes U, Bridges E, McIntyre A, Fielding BA, Harris AL. Fatty acid-binding protein 4, a point of convergence for angiogenic and metabolic signaling pathways in endothelial cells. J Biol Chem. 2014;289(33):23168–76.
122. Lee MY, Tse HF, Siu CW, Zhu SG, Man RY, Vanhoutte PM. Genomic changes in regenerated porcine coronary arterial endothelial cells. Arterioscler Thromb Vasc Biol. 2007;27(11):2443–9.
123. Han Q, Yeung SC, Ip MS, Mak JC. Effects of intermittent hypoxia on A-/E-FABP expression in human aortic endothelial cells. Int J Cardiol. 2010;145(2):396–8.
124. Daly C, Wong V, Burova E, et al. Angiopoietin-1 modulates endothelial cell function and gene expression via the transcription factor FKHR (FOXO1). Genes Dev. 2004;18(9):1060–71.
125. Lee MY, Li H, Xiao Y, Zhou Z, Xu A, Vanhoutte PM. Chronic administration of BMS309403 improves endothelial function in apolipoprotein E-deficient mice and in cultured human endothelial cells. Br J Pharmacol. 2011;162(7):1564–76.
126. Ha MK, Soo Cho J, Baik OR, Lee KH, Koo HS, Chung KY. Caenorhabditis elegans as a screening tool for the endothelial cell-derived putative aging-related proteins detected by proteomic analysis. Proteomics. 2006;6(11):3339–51.
127. Lee MY, Wang Y, Vanhoutte PM. Senescence of cultured porcine coronary arterial endothelial cells is associated with accelerated oxidative stress and activation of NFkB. J Vasc Res. 2010;47(4):287–98.
128. Tanaka M, Furuhashi M, Okazaki Y, et al. Ectopic expression of fatty acid-binding protein 4 in the glomerulus is associated with proteinuria and renal dysfunction. Nephron Clin Pract. January 9, 2015. doi: 10.1159/000368412. [Epub ahead of print]
129. Kamijo A, Kimura K, Sugaya T, et al. Urinary fatty acid-binding protein as a new clinical marker of the progression of chronic renal disease. J Lab Clin Med. 2004;143(1):23–30.
130. Noiri E, Doi K, Negishi K, et al. Urinary fatty acid-binding protein 1: an early predictive biomarker of kidney injury. Am J Physiol Renal Physiol. 2009;296(4):F669–79.
131. Okazaki Y, Furuhashi M, Tanaka M, et al. Urinary excretion of fatty acid-binding protein 4 is associated with albuminuria and renal dysfunction. PLoS One. 2014;9(12):e115429.
132. Ghelfi E, Karaaslan C, Berkelhamer S, Akar S, Kozakewich H, Cataltepe S. Fatty acid-binding proteins and peribronchial angiogenesis in bronchopulmonary dysplasia. Am J Respir Cell Mol Biol. 2011;45(3):550–6.
133. Maver A, Medica I, Peterlin B. Search for sarcoidosis candidate genes by integration of data from genomic, transcriptomic and proteomic studies. Med Sci Monit. 2009;15(12):SR22–8.
134. Biron-Shental T, Schaiff WT, Ratajczak CK, Bildirici I, Nelson DM, Sadovsky Y. Hypoxia regulates the expression of fatty acid-binding proteins in primary term human trophoblasts. Am J Obstet Gynecol. 2007;197(5):e511–6.
135. Scifres CM, Chen B, Nelson DM, Sadovsky Y. Fatty acid binding protein 4 regulates intracellular lipid accumulation in human trophoblasts. J Clin Endocrinol Metab. 2011;96(7):E1083–91.
136. Makkar A, Mishima T, Chang G, Scifres C, Sadovsky Y. Fatty acid binding protein-4 is expressed in the mouse placental labyrinth, yet is dispensable for placental triglyceride accumulation and fetal growth. Placenta. 2014;35(10):802–7.
137. Nourani MR, Owada Y, Kitanaka N, et al. Occurrence of immunoreactivity for adipocyte-type fatty acid binding protein in degenerating granulosa cells in atretic antral follicles of mouse ovary. J Mol Histol. 2005;36(8–9):491–7.
138. Hu W, Qiao J. Expression and regulation of adipocyte fatty acid binding protein in granulosa cells and its relation with clinical characteristics of polycystic ovary syndrome. Endocrine. 2011;40(2):196–202.
139. Wang J, Tang J, Wang B, et al. FABP4: a novel candidate gene for polycystic ovary syndrome. Endocrine. 2009;36(3):392–6.
140. Nieman KM, Kenny HA, Penicka CV, et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med. 2011;17(11):1498–503.
141. Bennett JH, Shousha S, Puddle B, Athanasou NA. Immunohistochemical identification of tumours of adipocytic differentiation using an antibody to aP2 protein. J Clin Pathol. 1995;48(10):950–4.
142. Cataltepe O, Arikan MC, Ghelfi E, et al. Fatty acid binding protein 4 is expressed in distinct endothelial and non-endothelial cell populations in glioblastoma. Neuropathol Appl Neurobiol. 2012;38(5):400–10.
143. Ohlsson G, Moreira JM, Gromov P, Sauter G, Celis JE. Loss of expression of the adipocyte-type fatty acid-binding protein (A-FABP) is associated with progression of human urothelial carcinomas. Mol Cell Proteomics. 2005;4(4):570–81.
144. Abdelwahab SA, Owada Y, Kitanaka N, et al. Enhanced expression of adipocyte-type fatty acid binding protein in murine lymphocytes in response to dexamethasone treatment. Mol Cell Biochem. 2007;299(1–2):99–107.
145. Lehmann F, Haile S, Axen E, et al. Discovery of inhibitors of human adipocyte fatty acid-binding protein, a potential type 2 diabetes target. Bioorg Med Chem Lett. 2004;14(17):4445–8.
146. Ringom R, Axen E, Uppenberg J, Lundback T, Rondahl L, Barf T. Substituted benzylamino-6-(trifluoromethyl)pyrimidin-4(1H)-ones: a novel class of selective human A-FABP inhibitors. Bioorg Med Chem Lett. 2004;14(17):4449–52.
147. Sulsky R, Magnin DR, Huang Y, et al. Potent and selective biphenyl azole inhibitors of adipocyte fatty acid binding protein (aFABP). Bioorg Med Chem Lett. 2007;17(12):3511–5.
148. Hertzel AV, Hellberg K, Reynolds JM, et al. Identification and characterization of a small molecule inhibitor of fatty acid binding proteins. J Med Chem. 2009;52(19):6024–31.
149. Barf T, Lehmann F, Hammer K, et al. N-Benzyl-indolo carboxylic acids: design and synthesis of potent and selective adipocyte fatty-acid binding protein (A-FABP) inhibitors. Bioorg Med Chem Lett. 2009;19(6):1745–8.
150. Lan H, Cheng CC, Kowalski TJ, et al. Small-molecule inhibitors of FABP4/5 ameliorate dyslipidemia but not insulin resistance in mice with diet-induced obesity. J Lipid Res. 2011;52(4):646–56.
151. Furuhashi M, Tuncman G, Görgün CZ, et al. Treatment of diabetes and atherosclerosis by inhibiting fatty-acid-binding protein aP2. Nature. 2007;447(7147):959–65.
152. Auwerx J. PPARgamma, the ultimate thrifty gene. Diabetologia. 1999;42(9):1033–49.