Fatty acid-binding proteins: Role in metabolic diseases and potential as drug targets

Nature Reviews Drug Discovery

Volumn 7, Issue 6, 2008, Pages 489-503

  Furuhashi, Masato ^a   Hotamisligil, Gökhan S ^a  

^a HARVARD SCHOOL OF PUBLIC HEALTH   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ADIPOCYTE FATTY ACID BINDING PROTEIN; BMS 309403; CARBAZOLE DERIVATIVE; CARRIER PROTEIN; EPIDERMAL FATTY ACID BINDING PROTEIN; FATTY ACID BINDING PROTEIN; FATTY ACID BINDING PROTEIN 1; FATTY ACID BINDING PROTEIN 2; FATTY ACID BINDING PROTEIN 3; FATTY ACID BINDING PROTEIN 4; FATTY ACID BINDING PROTEIN 5; FATTY ACID BINDING PROTEIN 6; FATTY ACID BINDING PROTEIN 7; FATTY ACID BINDING PROTEIN 8; FATTY ACID BINDING PROTEIN 9; FATTY ACID BINDING PROTEIN INHIBITOR; INSULIN; PROTEIN INHIBITOR;

ADIPOCYTE; ATHEROSCLEROSIS; BINDING AFFINITY; CRYSTAL STRUCTURE; DIABETES MELLITUS; DRUG MECHANISM; DRUG POTENCY; DRUG TARGETING; FATTY LIVER; GENE OVEREXPRESSION; HUMAN; INSULIN RESISTANCE; INSULIN SENSITIVITY; LIPID METABOLISM; LIPID STORAGE; LIPID TRANSPORT; MACROPHAGE; METABOLIC DISORDER; NONHUMAN; OBESITY; PRIORITY JOURNAL; PROTEIN FUNCTION; PROTEIN LOCALIZATION; PROTEIN STRUCTURE; REVIEW; SIGNAL TRANSDUCTION; TISSUE DISTRIBUTION;

ANIMALS; BINDING SITES; FATTY ACID-BINDING PROTEINS; HUMANS; LIGANDS; LIPID METABOLISM; METABOLIC DISEASES; MODELS, MOLECULAR; ORGAN SPECIFICITY;

EID: 44449118921     PISSN: 14741776     EISSN: 14741784     Source Type: Journal    
DOI: 10.1038/nrd2589     Document Type: Review

References (101)

1. Hotamisligil, G. S. Inflammation and metabolic disorders. Nature 444, 860-867 (2006).
2. Saltiel. A. R. & Kahn, C. R. Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414, 799-806 (2001).
3. Funk, C. D. Prostaglandins and leukotrienes: Advances in eicosanoid biology. Science 294, 1671-1875 (2001).
4. Serhan, C. N. Resolution phase of inflammation: Novel endogenous anti-inflammatory and proresolving lipid mediators and pathways. Annu. Rev. Immunol. 25, 101-137 (2007).
5. Haunerland, N. H. & Spener, F. Fatty acid-binding proteins - insights from genetic manipulations. Prog. Lipid Res. 43, 328-349 (2004).
6. Chmurzynska, A. The multigene family of fatty acid-binding proteins (FABPs): Function, structure and polymorphism. J. Appl. Genet. 47, 39-48 (2006).
7. Makowski, L & Hotamisligil, G. S. The role of fatty acid binding proteins in metabolic syndrome and atherosclerosis. Curr. Opin. Lipidol. 16, 543-548 (2005).
8. Coe, N. R. & Bemlohr, D. A. Physiological properties and functions of intracellular fatty acid-binding proteins. Biochim. Biophys. Acta 1391, 287-306 (1998).
9. Zimmerman, A. W. & Veerkamp, J. H. New insights into the structure and function of fatty acid-binding proteins. Cell. Mol. Life Sci. 59, 1096-1116 (2002).
10. Ockner, R. K., Manning, J. A., Poppenhausen, R. B. & Ho, W. K. A binding protein for fatty acids in cytosol of intestinal mucosa, liver, myocardium, and other tissues. Science 177, 56-58 (1972).
11. ll Veerkamp, J. H. & van Moerkerk, H. T. Fatty acid-binding protein and its relation to fatty acid oxidation. Mol Cell Biochem. 123, 101-106 (1993).
12. Zanotti, G. Muscle fatty acid-binding protein. Biochim. Biophys. Acta 1441, 94-105 (1999).
13. 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. 382, 239-245 (2004).
14. Motojima, K. Differential effects of PPARα. activators on induction of ectopic expression of tissue-specific fatty acid binding protein genes in the mouse liver. Int. J. Biochem. Cell Biol. 32, 1085-1092 (2000).
15. Tan, N. S. et al. Selective cooperation between fatty acid binding proteins and peroxisome proliferator-activated receptors in regulating transcription. Mol. Cell Biol. 22, 5114-5127 (2002).
16. Wolfrum, C., Borrmann, C. M., Borchers, T & Spener, F. Fatty acids and hypolipidemic drugs regulate peroxisome proliferator-activated receptors α- and γ-mediated gene expression via liver fatty acid binding protein: A signaling path to the nucleus. Proc. Natl Acad. Sci. USA 98, 2323-2328 (2001).
17. Ayers, S. D., Nedrow, K. L. Gillilan, R. E. & Noy, N. Continuous nucleocytoplasmic shuttling underlies transcriptional activation of PPARγ by FABP4. Biochemistry 46, 6744-6752 (2007).
18. Makowski, L, Brittingham, K. C., Reynolds, J.M., Suttles, J. & Hotamisligil, G. S. The fatty acid-binding protein, aP2, coordinates macrophage cholesterol trafficking and inflammatory activity. Macrophage expression of aP2 impacts peroxisome proliferator-activated receptor γ and 1KB kinase activities. J. Biol. Chem. 280, 12888-12895 (2005).
19. Balendiran, G. K. et al. Crystal structure and thermodynamic analysis of human brain fatty acid-binding protein. J. Biol. Chem. 275, 27045-27054 (2000).
20. Ek, B. A., Cistola. D. P., Hamilton. J. A., Kaduce, T. L. & Spector, A. A. Fatty acid binding proteins reduce 154-lipoxygenase-induced oxygenation of linoleic acid and arachidonic acid. Biochim. Biophys. Acta 1346, 75-85 (1997).
21. Zimmer, J. S., Dyckes, D. F., Bernlohr. D. A. & Murphy, R. C. Fatty acid binding proteins stabilize leukotriene A4: Competition with arachidonic acid but not other lipoxygenase products. J. Lipid Res. 45, 2138-2144 (2004).
22. Shen. W J., Sridhar, K., Bernlohr. D. A. & Kraemer, F. B. Interaction of rat hormone-sensitive lipase with adipocyte lipid-binding protein. Proc. Natl Acad. Sci. USA 96, 5528-5532 (1999).
23. -/- mice. Diabetes 48, 1987-1994 (1999).
24. Coe, N. R., Simpson, M. A. & Bernlohr, D. A. Targeted disruption of the adipocyte lipid-binding protein (aP2 protein) gene impairs fat cell lipolysis and increases cellular fatty acid levels. J. Lipid Res. 40, 967-972 (1999).
25. Hertzel, A. V., Bennaars-Eiden, A. & Bernlohr, D. A. Increased lipolysis in transgenic animals overexpressing the epithelial fatty acid binding protein in adipose cells. J. Lipid Res. 43, 2105-2111 (2002).
26. Gillian, R. E., Ayers, S. D. & Noy, N. Structural basis for activation of fatty acid-binding protein 4. J. Mol. Biol. 372, 1246-1260 (2007).
27. Rolf, B. et al. Analysis of the ligand binding properties of recombinant bovine liver-type fatty acid binding protein. Biochim. Biophys. Acta 1259, 245-253 (1995).
28. Martin, G. G. et al. Decreased liver fatty acid binding capacity and altered liver lipid distribution in mice lacking the liver fatty acid-binding protein gene. J. Biol. Chem. 278, 21429-21438 (2003).
29. Newberry, E. P. et al. Decreased hepatic triglyceride accumulation and altered fatty acid uptake in mice with deletion of the liver fatty acid-binding protein gene. J. Biol. Chem. 278, 51664-51672 (2003).
30. Martin, G. G. et al. Liver fatty acid binding protein gene ablation potentiates hepatic cholesterol accumulation in cholesterol-fed female mice. Am. J. Physiol. Gastrointest. Liver Physiol. 290 G36-G48 (2006).
31. Newberry, E. P., Xie, Y., Kennedy, S. M., Luo, J. & Davidson, N. O. Protection against Western diet-induced obesity and hepatic steatosis in liver fatty acid-binding protein knockout mice. Hepatology 44 1191-1205 (2006).
32. -/- mice is abrogated with SF, but not PUFA, feeding and attenuated after cholesterol supplementation. Am. J. Physiol. Gastrointest. Liver Physiol. 294, G307-G314 (2008).
33. Kamijo-Ikemori, A., Sugaya, T. & Kimura, K. Urinary fatty acid binding protein in renal disease. Clin. Chim. Acta 374, 1-7 (2006).
34. Agellon, L. B., Toth, M. J. & Thomson. A. B. Intracellular lipid binding proteins of the small intestine Mol. Cell Biochem. 239, 79-82 (2002).
35. Vassileva, G., Huwyler, L, Poirier, K., Agellon, L. B. & Toth, M. J. The intestinal fatty acid binding protein is not essential for dietary fat absorption in mice. FASEB J. 14, 2040-2046 (2000).
36. Bar, L. J. et al. An amino acid substitution in the human intestinal fatty acid binding protein is associated with increased fatty acid binding, increased fat oxidation, and insulin resistance. J. Clin. Invest. 95, 1281-1287 (1995).
37. Furuhashi, M. et al. Fenofibrate improves insulin sensitivity in connection with intramuscular lipid content, muscle fatty acid-binding protein, and β-oxidation in skeletal muscle. J. Endocrinol. 174, 321-329 (2002).
38. Binas, B., Danneberg, H., McWhir, J., Mullins, L & Clark, A. J. Requirement for the heart-type fatty acid binding protein in cardiac fatty acid utilization. FASEB J. 13, 805-812 (1999).
39. Schaap, F. G., Binas, B., Danneberg, H., van der Vusse, G. J. & Glatz, J. F Impaired long-chain fatty acid utilization by cardiac myocytes isolated from mice lacking the heart-type fatty acid binding protein gene. Circ. Res. 85, 329-337 (1999).
40. Binas, B. et al. A null mutation in H-FABP only partially inhibits skeletal muscle fatty acid metabolism. Am. J. Physiol. Endocrinol. Metab. 285, E481-E489 (2003).
41. Binas, B. et al. Hormonal induction of functional differentiation and mammary-derived growth inhibitor expression in cultured mouse mammary gland explants. In Vitro Cell Dev. Biol. 28A, 625-634 (1992).
42. Bohmer. F D. et al. Identification of a polypeptide growth inhibitor from bovine mammary gland. Sequence homology to fatty acid- and retinoid-binding proteins. J. Biol. Chem. 262, 15137-15143 (1987).
43. Specht, B. et al. Mammary derived growth inhibitor is not a distinct protein but a mix of heart-type and adipocyte-type fatty acid-binding protein. J. Biol. Chem. 271, 19943-19949 (1996).
44. Huynh, H. T., Larsson, C., Narod, S. & Pollak, M. Tumor suppressor activity of the gene encoding mammary-derived growth inhibitor. Cancer Res. 55, 2225-2231 (1995).
45. Clark, A. J., Neil, C., Gusterson, B., McWhir, J. & Binas, B. Deletion of the gene encoding H-FABP/MDGI has no overt effects in the mammary gland. Transgenic Res. 9, 439-444 (2000).
46. Binas, B., Gusterson, B, Wallace R. & Clark, A. J. Epithelial proliferation and differentiation in the mammary gland do not correlate with cFABP gene expression during early pregnancy. Dev. Genet. 17, 167-175 (1995).
47. 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. 24, 195-201 (1991).
48. Setsuta, K. et al. Use of cytosolic and myofibril markers in the detection of ongoing myocardial damage in patients with chronic heart failure. Am. J. Med. 113, 717-722 (2002).
49. Furuhashi, M. 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. 93, C69-C74 (2003).
50. Pelsers, M. M., Hermens, W. T. & Glatz, J. F. Fatty acid-binding proteins as plasma markers of tissue injury. Clin. Chim. Acta 352, 15-35 (2005).
51. Spiegelman, B. M., 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. 258, 10083-10089 (1983).
52. Hunt, C. R., Ro, J. H., Dobson, D. E., Min, H. Y. & Spiegelman, B. M. Adipocyte P2 gene: Developmental expression and homology of 5-pm-flanking sequences among fat cell-specific genes. Proc. Natl Acad. Sci. USA 83, 3786-3790 (1986).
53. Hotamisligil, G. S. et al. Uncoupling of obesity from insulin resistance through a targeted mutation in aP2, the adipocyte fatty acid binding protein. Science 274, 1377-1379 (1996).
54. Uysal, K. T., Scheja, L., Wiesbrock, S. M., Bonner-Weir, S. & Hotamisligil, G. S. Improved glucose and lipid metabolism in genetically obese mice lacking aP2. Endocrinology 141, 3388-3396 (2000).
55. Makowski, L. et al. Lack of macrophage fatty-acid-binding protein aP2 protects mice deficient in apolipoprotein E against atherosclerosis. Nature Med. 7, 699-705 (2001).
56. Pelton, P. D., Zhou, L., Demarest, K. T. & Burris, T. P. PPARγ activation induces the expression of the adipocyte fatty acid binding protein gene in human monocytes. Biochem. Biophys. Res. Commun. 261, 456-458 (1999).
57. Fu, Y., Luo, N. & Lopes-Virella, M. F. Oxidized LDL induces the expression of ALBP/aP2 mRNA and protein in human THP-1 macrophages. J. Lipid Res. 41, 2017-2023 (2000).
58. Fu, Y., Luo, N., Lopes-Virella, M. F. & Garvey, W. T. The adipocyte lipid binding protein (ALBP/aP2) gene facilitates foam cell formation in human THP-1 macrophages. Atherosclerosis 165, 259-269 (2002).
59. Kazemi, M. R., McDonald, C. M., Shigenaga, J. K., Grunfeld, C. & Feingold, K. R. 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. 25, 1220-1224 (2005).
60. Ralph, M. S. et al. Regulation of dendritic cell function and T cell priming by the fatty acid-binding protein AP2. J. Immunol. 177, 7794-7801 (2006).
61. Llaverias, G. et al. Atorvastatin reduces CD68, FABP4, and HBP expression in oxLDL-treated human macrophages. Biochem. Biophys Res. Commun. 318, 265-274 (2004).
62. Shum, B. O. et al. The adipocyte fatty acid-binding protein aP2 is required in allergic airway inflammation. J. Clin. Invest. 116 2183-2192 (2006).
63. Boord, J. B. et al. Adipocyte fatty acid-binding protein, aP2, alters late atherosclerotic lesion formation in severe hypercholesterolemia. Arterioscler. Thromb. Vasc. Biol. 22, 1686-1691 (2002).
64. Bennett, J. H., Shousha, S., Puddle, B. & Athanasou, N. A. Immunohistochemical identification of tumours of adipocytic differentiation using an antibody to aP2 protein. J. Clin. Pathol. 48, 950-954 (1995).
65. Ohlsson, G., Moreira, J. M., Gromov, P., Sauter, G. & Celis, J. E. Loss of expression of the adipocyte-type fatty acid-binding protein (A-FABP) is associated with progression of human urothelial carcinomas. Mol. Cell Proteomics 4, 570-581 (2005).
66. Xu, A. et al. Adipocyte fatty acid-binding protein is a plasma biomarker closely associated with obesity and metabolic syndrome. Clin. Chem. 52, 405-413 (2006).
67. Tso, A. W. 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 30, 2667-2272 (2007).
68. Yeung, D. C. et al. Serum adipocyte fatty acid-binding protein levels were independently associated with carotid atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 27, 1796-1802 (2007).
69. Simpson, M. A., LiCata, V. J., Ribarik Coe, N. & Bernlohr, D. A. Biochemical and biophysical analysis of the intracellular lipid binding proteins of adipocytes. Mol. Cell Biochem. 192, 33-40 (1999).
70. Maeda, K. et al. Role of the fatty acid binding protein mall in obesity and insulin resistance. Diabetes 52, 300-307 (2003).
71. Owada, Y., Suzuki, I., Noda, T. & Kondo, H. Analysis on the phenotype of E-FABP-gene knockout mice. Mol. Cell Biochem. 239, 83-86 (2002).
72. Jing, C. et al. Human cutaneous fatty acid-binding protein induces metastasis by up-regulating the expression of vascular endothelial growth factor gene in rat Rama 37 model cells. Cancer Res. 61 4357-4364 (2001).
73. Schug, T. T., Berry D. C., Shaw, N. S., Travis, S. N. & Noy, N. Opposing effects of retinoic acid on cell growth result from alternate activation of two different nuclear receptors. Cell 129, 723-733 (2007).
74. Veerkamp, J. H. & Zimmerman, A. W. Fatty acid-binding proteins of nervous tissue. J. Mol. Neurosci. 16, 133-142; discussion 151-157 (2001).
75. Feng, L., Hatten, M. E. & Heintz, N. Brain lipid-binding protein (BLBP): a novel signaling system in the developing mammalian CNS. Neuron 12, 895-908 (1994).
76. Xu, L. Z., Sanchez, R., Sali, A. & Heintz, N. Ligand specificity of brain lipid-binding protein. J. Biol. Chem. 271, 24711-24719 (1996).
77. Sanchez-Font, M. F., Bosch-Comas, A., Gonzalez-Duarte, R. & Marfany, G. Overexpression of FABP7 in Down syndrome fetal brains is associated with PKNOX1 gene-dosage imbalance. Nucleic Acids Res. 31, 2769-2777 (2003).
78. Watanabe, A. et al. Fabp7 maps to a quantitative trait locus for a schizophrenia endophenotype. PLoS Biol. 5, 2469-2483 (2007).
79. Owada, Y. et al. Altered emotional behavioral responses in mice lacking brain-type fatty acid-binding protein gene. Eur. J. Neurosci. 24: 175-187 (2006).
80. Shi, Y. et al. Antitumor activity of the novel human breast cancer growth inhibitor, mammary-derived growth inhibitor-related gene. MRG. Cancer Res. 57, 3084-3091 (1997).
81. Hohoff, C. & Spener, F. Correspondence re: Y. E. Shi et al., Antitumor activity of the novel human breast cancer growth inhibitor, mammary-derived growth inhibitor-related gene, MRG. Cancer Res. 57, 3084-3091, 1997. Cancer Res. 58, 4015-4017 (1998).
82. Maeda, K. et al. Adipocyte/macrophage fatty acid binding proteins control integrated metabolic responses in obesity and diabetes. Cell. Metab. 1, 107-119 (2005).
83. Cao, H. et al. Regulation of metabolic responses by adipocyte/ macrophage fatty acki-binding proteins in leptin-deficent mice. Diabetes 55, 1915-1922 (2006).
84. Boord, J. B. et al. Combined adipocyte-macrophage fatty acid binding protein deficiency improves metabolism, atherosclerosis, and survival in apolipoprotein E-deficient mice. Circulation 110 1492-1498 (2004).
85. Weisberg, S. P. et al. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 1796-1808 (2003).
86. Xu, H. et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Invest. 112, 1821-1830 (2003).
87. Lehmann, F. et al. Discovery of inhibitors of human adipocyte fatty add-binding protein, a potential type 2 diabetes target. Bioorg. Med. Chem. Lett. 14, 4445-4448 (2004).
88. Ringom, R. et al. Substituted benzylamino-6-(trifluoromethyl) pyrimidin-4(1 H) ones: A novel class of selective human A-FABP inhibitors. Bioorg. Med. Chem. Lett. 14, 4449-4452 (2004).
89. Sulsky, R. et al. Potent and selective biphenyl azole inhibitors of adipocyte fatty acid binding protein (aFABP). Bioorg. Med. Chem. Lett. 17, 3511-3515 (2007).
90. Furuhashi, M. et al. Treatment of diabetes and atherosclerosis by inhibiting fatty-acid-binding protein aP2. Nature 447, 959-965 (2007).
91. Hirosumi, J. et al. A central role for JNK in obesity and insulin resistance. Nature 420, 333-336 (2002).
92. Tuncman, G. et al. Functional in vivo interactions between JNK1 and JNK2 isoforms in obesity and insulin resistance. Proc. Natl Acad. Sci. USA 103, 10741-10746 (2006).
93. Tuncman, G. 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. USA 103, 6970-6975 (2006).
94. Auwerx, J. PPARγ, the ultimate thrifty gene. Diabetologia 42 1033-1049 (1999).
95. Esteves, A. & Ehrlich, R. Invertebrate intracellular fatty acid binding proteins. Comp. Biochem. Physiol. C Toxicol. Pharmacol. 142, 262-274 (2006).
96. Thompson, J., Winter, N., Terwey, D., Bratt, J. & Banaszak, L. The crystal structure of the liver fatty acid-binding protein. A complex with two bound oleates. J. Biol. Chem. 272, 7140-7150 (1997).
97. Sacchettini, J. C., Gordon, J. I. & Banaszak, L. J. Crystal structure of rat intestinal fatty-acid-binding protein. Refinement and analysis of the Escherichia coli-derived protein with bound palmitate. J. Mol. Biol. 208, 327-339 (1989).
98. Zanotti, G., Scapin, G., Spadon, P., Veerkamp, J. H. & Sacchettini, J. C. Three-dimensional structure of recombinant human muscle fatty acid-binding protein. J. Biol. Chem. 267, 18541-18550 (1992).
99. Flower, D. R., North, A. C. & Attwood, T. K. Structure and sequence relationships in the lipocalins and related proteins. Protein Sci. 2, 753-761 (1993).
100. Smith, A. J., Thompson, B. R., Sanders, M. A. & Bernlohr, D. A. Interaction of the adipocyte fatty acid-binding protein with the hormone-sensitive lipase. Regulation by fatty acids and phosphorylation. protein. J. Biol. Chem. 282, 32424-32432 (2007).
101. Furuhashi, M. et al. Regulated interactions of bone marrow-derived and stromal elements in the metabolic actions of adipocyte/macrophage fatty acid-binding proteins. J. Clin. Invest. (in the press).