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

Key Points

  • Fatty acids function both as an energy source and as metabolic signalling molecules and affect many vital processes. This complexity combined with the chemical characteristics of lipids present many challenges in their trafficking, compartmentalization and specific target engagement properties within and between cells.

  • Intracellular lipid chaperones dictate the destiny of lipids. Also known as fatty acid-binding proteins (FABPs), these are a group of proteins that coordinate lipid trafficking and signalling in cells, and some isoforms are also strongly linked to metabolic and inflammatory pathways.

  • At least nine FABPs have been identified to date, which exhibit unique patterns of tissue expression. The family contains liver (L-), intestinal (I-), heart (H-), adipocyte (A-), epidermal (E-), ileal (Il-), brain (B-), myelin (M-) and testis (T-) FABPs.

  • Adipocytes and macrophages jointly express two FABPs: A-FABP (also known as aP2/FABP4) and E-FABP (also known as mal1/FABP5), which are the best-studied FABPs. They play a central role in many aspects of metabolic diseases including obesity, diabetes, fatty liver disease, asthma and atherosclerosis. The loss-of-function genetic models of these isoforms are essentially free of metabolic disease and indicate the therapeutic potential of targeting these proteins in metabolic disease. In fact, humans with a genetic variation causing aP2 haploinsufficiency are resistant against type 2 diabetes and cardiovascular disease.

  • Recently, it has been shown that it is possible to rationally design an orally active, high affinity, potent and selective synthetic inhibitor of A-FABP. Administration of this inhibitor markedly reduced the extent of atherosclerosis and improved insulin sensitivity in distinct genetic and/or dietary models of atherosclerosis and type 2 diabetes.

Abstract

Lipids are vital components of many biological processes and crucial in the pathogenesis of numerous common diseases, but the specific mechanisms coupling intracellular lipids to biological targets and signalling pathways are not well understood. This is particularly the case for cells burdened with high lipid storage, trafficking and signalling capacity such as adipocytes and macrophages. Here, we discuss the central role of lipid chaperones — the fatty acid-binding proteins (FABPs) — in lipid-mediated biological processes and systemic metabolic homeostasis through the regulation of diverse lipid signals, and highlight their therapeutic significance. Pharmacological agents that modify FABP function may provide tissue-specific or cell-type-specific control of lipid signalling pathways, inflammatory responses and metabolic regulation, potentially providing a new class of drugs for diseases such as obesity, diabetes and atherosclerosis.

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Figure 1: Putative functions of FABP in the cell.
Figure 2: Functions of A-FABP in the adipocyte and macrophage.
Figure 3: Crystal structure of the synthetic A-FABP inhibitor BMS309403 bound to human A-FABP.

References

  1. Hotamisligil, G. S. Inflammation and metabolic disorders. Nature 444, 860–867 (2006).

    CAS  PubMed  Google Scholar 

  2. Saltiel, A. R. & Kahn, C. R. Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414, 799–806 (2001).

    CAS  PubMed  Google Scholar 

  3. Funk, C. D. Prostaglandins and leukotrienes: advances in eicosanoid biology. Science 294, 1671–1875 (2001).

    Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  5. Haunerland, N. H. & Spener, F. Fatty acid-binding proteins — insights from genetic manipulations. Prog. Lipid Res. 43, 328–349 (2004).

    CAS  PubMed  Google Scholar 

  6. Chmurzynska, A. The multigene family of fatty acid-binding proteins (FABPs): function, structure and polymorphism. J. Appl. Genet. 47, 39–48 (2006).

    PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Coe, N. R. & Bernlohr, D. A. Physiological properties and functions of intracellular fatty acid-binding proteins. Biochim. Biophys. Acta 1391, 287–306 (1998).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  11. 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).

    CAS  PubMed  Google Scholar 

  12. Zanotti, G. Muscle fatty acid-binding protein. Biochim. Biophys. Acta 1441, 94–105 (1999).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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). This excellent manuscript describes a potential and interesting mechanism for the action of L-FABP as a regulator of specific gene-expression programs.

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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 IκB kinase activities. J. Biol. Chem. 280, 12888–12895 (2005).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  20. Ek, B. A., Cistola, D. P., Hamilton, J. A., Kaduce, T. L. & Spector, A. A. Fatty acid binding proteins reduce 15-lipoxygenase-induced oxygenation of linoleic acid and arachidonic acid. Biochim. Biophys. Acta 1346, 75–85 (1997).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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). In this study, the authors demonstrate an interaction between HSL and A-FABP and suggest that this interaction might serve to deliver a lipid ligand to a catalytic site and regulate the enzymatic activity.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Scheja, L. et al. Altered insulin secretion associated with reduced lipolytic efficiency in aP2−/− mice. Diabetes 48, 1987–1994 (1999).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  32. Newberry, E. P. et al. Diet-induced obesity and hepatic steatosis in L-Fabp−/− mice is abrogated with SF, but not PUFA, feeding and attenuated after cholesterol supplementation. Am. J. Physiol. Gastrointest. Liver Physiol. 294, G307–G314 (2008).

    CAS  PubMed  Google Scholar 

  33. Kamijo-Ikemori, A., Sugaya, T. & Kimura, K. Urinary fatty acid binding protein in renal disease. Clin. Chim. Acta 374, 1–7 (2006).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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). In this study, the authors identified a biochemical entity, which turned out to be an FABP, as a regulator of growth. This paper is critical, despite many disagreements, in raising the possibility that FABPs could exit the cells and regulate other cells, an idea that has not been sufficiently appreciated.

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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′-flanking sequences among fat cell-specific genes. Proc. Natl Acad. Sci. USA 83, 3786–3790 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  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). This is a crucial paper describing the first loss-of-function model of any FABP family members, and demonstrating a role for A-FABP in metabolic homeostasis.

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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). An important study describing the presence and function of A-FABP in the macrophages, which has not been recognized for a long time, and the central importance of macrophage A-FABP in atherosclerosis.

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  60. Rolph, 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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  70. Maeda, K. et al. Role of the fatty acid binding protein mal1 in obesity and insulin resistance. Diabetes 52, 300–307 (2003).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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). This excellent study demonstrates the impact of E-FABP in regulating survival responses to retinoic acid through interactions with a nuclear hormone receptor.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Veerkamp, J. H. & Zimmerman, A. W. Fatty acid-binding proteins of nervous tissue. J. Mol. Neurosci. 16, 133–142; discussion 151–157 (2001).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  76. Xu, L. Z., Sanchez, R., Sali, A. & Heintz, N. Ligand specificity of brain lipid-binding protein. J. Biol. Chem. 271, 24711–24719 (1996).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Watanabe, A. et al. Fabp7 maps to a quantitative trait locus for a schizophrenia endophenotype. PLoS Biol. 5, 2469–2483 (2007).

    CAS  Google Scholar 

  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).

    PubMed  Google Scholar 

  80. Shi, Y. E. 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).

    CAS  PubMed  Google Scholar 

  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).

    Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  83. Cao, H. et al. Regulation of metabolic responses by adipocyte/macrophage fatty acid-binding proteins in leptin-deficient mice. Diabetes 55, 1915–1922 (2006).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Weisberg, S. P. et al. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 1796–1808 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Lehmann, F. et al. Discovery of inhibitors of human adipocyte fatty acid-binding protein, a potential type 2 diabetes target. Bioorg. Med. Chem. Lett. 14, 4445–4448 (2004).

    CAS  PubMed  Google Scholar 

  88. Ringom, R. et al. Substituted benzylamino-6-(trifluoromethyl)pyrimidin-4(1H)-ones: a novel class of selective human A-FABP inhibitors. Bioorg. Med. Chem. Lett. 14, 4449–4452 (2004).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  90. Furuhashi, M. et al. Treatment of diabetes and atherosclerosis by inhibiting fatty-acid-binding protein aP2. Nature 447, 959–965 (2007). An important manuscript demonstrating the feasibility of developing a synthetic FABP inhibitor that could mimic the phenotype of genetic FABP-deficiency by increasing insulin sensitivity and protecting against atherosclerosis.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Hirosumi, J. et al. A central role for JNK in obesity and insulin resistance. Nature 420, 333–336 (2002).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Auwerx, J. PPARγ, the ultimate thrifty gene. Diabetologia 42, 1033–1049 (1999).

    CAS  PubMed  Google Scholar 

  95. Esteves, A. & Ehrlich, R. Invertebrate intracellular fatty acid binding proteins. Comp. Biochem. Physiol. C Toxicol. Pharmacol. 142, 262–274 (2006).

    PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

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Acknowledgements

Studies on FABPs and related areas in the Hotamisligil laboratory are supported by the National Institutes of Health, USA, and the American Diabetes Association. M.F. has been supported by fellowships from the Japan Society for the Promotion of Science and the American Diabetes Association. We would like to acknowledge the invaluable contributions made by past and current laboratory members and long-standing collaborations, particularly with M. Linton and R. Parker. We also regret the inadvertent omission of many important references owing to space limitations.

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Correspondence to Gökhan S. Hotamisligil.

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Down's syndrome

obesity

type 2 diabetes

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Furuhashi, M., Hotamisligil, G. Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets. Nat Rev Drug Discov 7, 489–503 (2008). https://doi.org/10.1038/nrd2589

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