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Adipocyte/macrophage fatty acid binding proteins in metabolic syndrome

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Abstract

The link between inflammation and the development of insulin resistance, type 2 diabetes, and atherosclerosis has been uncovered in the past decade. Although the molecular mechanisms underlying the co-occurrence of these metabolic and inflammatory diseases are not fully understood, several molecular players, integrating stress and inflammatory responses with metabolic homeostasis, were discovered recently. One of these molecular integration sites is through the action of cytosolic lipid chaperones or fatty acid binding proteins (FABPs), which are common to adipocytes and macrophages. Furthermore, studies in a variety of genetic models demonstrated that the FABPs aP2 and mal1 are critical mediators of many components of metabolic syndrome in mice. These exciting findings raise the possibility that FABPs represent desirable therapeutic targets for metabolic syndrome. In this review, we describe the findings demonstrating FABP’s role in metabolic and inflammatory diseases and highlight recent advances in understanding the mechanisms of FABP function at the cellular and molecular level.

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References and Recommended Reading

  1. Hotamisligil GS: Inflammation and metabolic disorders. Nature 2006, 444:860–867.

    Article  PubMed  CAS  Google Scholar 

  2. Semenkovich CF: Insulin resistance and atherosclerosis. J Clin Invest 2006, 116:1813–1822.

    Article  PubMed  CAS  Google Scholar 

  3. Wellen KE, Hotamisligil GS: Inflammation, stress, and diabetes. J Clin Invest 2005, 115:1111–1119.

    Article  PubMed  CAS  Google Scholar 

  4. Makowski L, Hotamisligil GS: The role of fatty acid binding proteins in metabolic syndrome and atherosclerosis. Curr Opin Lipidol 2005, 16:543–548.

    Article  PubMed  CAS  Google Scholar 

  5. Tuncman G Erbay E, Hom X, et al.: A functional genetic variant at the fatty acid binding protein, aP2, locus reduces the risk for hypertriglyceridemia, type 2 diabetes and cardivascular disease. Proc Natl Acad Sci U S A 2005, 103:6970–6975.

    Article  Google Scholar 

  6. Tabas I: Consequences of cellular cholesterol accumulation: basic concepts and physiological implications. J Clin Invest 2002, 110:905–911.

    Article  PubMed  CAS  Google Scholar 

  7. Funk CD: Prostaglandins and leukotrienes: advances in eicosanoid biology. Science 2001, 294:1871–1875.

    Article  PubMed  CAS  Google Scholar 

  8. Stumvoll M, Goldstein BJ, van Haeften TW: Type 2 diabetes: principles of pathogenesis and therapy. Lancet 2005, 365:1333–1346.

    Article  PubMed  CAS  Google Scholar 

  9. Esteves A, Ehrlich R: Invertebrate intracellular fatty acid binding proteins. Comp Biochem Physiol C Toxicol Pharmacol 2006, 142:262–274.

    Article  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  11. Xu Z, Bernlohr DA, Banaszak LJ: Crystal structure of recombinant murine adipocyte lipid-binding protein. Biochemistry 1992, 31:3484–3492.

    Article  PubMed  CAS  Google Scholar 

  12. Reese-Wagoner A, Thompson J, Banaszak L: Structural properties of the adipocyte lipid binding protein. Biochim Biophys Acta 1999, 1441:106–116.

    PubMed  CAS  Google Scholar 

  13. Maeda K, Uysal KT, Makowski L, et al.: Role of the fatty acid binding protein mal1 in obesity and insulin resistance. Diabetes 2003, 52:300–307.

    Article  PubMed  CAS  Google Scholar 

  14. Makowski L, Brittingham KC, Reynolds JM, et al.: 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, 280:12888–12895.

    Article  PubMed  CAS  Google Scholar 

  15. 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, 1:107–119.

    Article  PubMed  CAS  Google Scholar 

  16. 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, 110:1492–1498.

    Article  PubMed  CAS  Google Scholar 

  17. Hotamisligil GS, Johnson RS, Distel RJ, et al.: Uncoupling of obesity from insulin resistance through a targeted mutation in aP2, the adipocyte fatty acid binding protein. Science 1996, 274:1377–1379.

    Article  PubMed  CAS  Google Scholar 

  18. Shaughnessy S, Smith ER, Kodukula S, et al.: Adipocyte metabolism in adipocyte fatty acid binding protein knockout mice (aP2-/-) after short-term high-fat feeding: functional compensation by the keratinocyte [correction of keritinocyte] fatty acid binding protein. Diabetes 2000, 49:904–911.

    Article  PubMed  CAS  Google Scholar 

  19. 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, 116:2183–2192.

    Article  PubMed  CAS  Google Scholar 

  20. 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, 7:699–705.

    Article  PubMed  CAS  Google Scholar 

  21. 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, 22:1686–1691.

    Article  PubMed  CAS  Google Scholar 

  22. 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, 165:259–269.

    Article  PubMed  CAS  Google Scholar 

  23. Hertzel AV, Bernlohr DA: The mammalian fatty acid-binding protein multigene family: molecular and genetic insights into function. Trends Endocrinol Metab 2000, 11:175–180.

    Article  PubMed  CAS  Google Scholar 

  24. Vassileva G, Huwyler L, Poirier K, et al.: The intestinal fatty acid binding protein is not essential for dietary fat absorption in mice. FASEB J 2000, 14:2040–2046.

    Article  PubMed  CAS  Google Scholar 

  25. Martin GG, Danneberg H, Kumar LS, 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 2003, 278:21429–21438.

    Article  PubMed  CAS  Google Scholar 

  26. Martin GG, Atshaves BP, McIntosh AL, et al.: Liver fatty acid binding protein gene ablation potentiates hepatic cholesterol accumulation in cholesterol-fed female mice. Am J Physiol Gastrointest Liver Physiol 2006, 290:G36–G48.

    Article  PubMed  CAS  Google Scholar 

  27. Newberry EP, Xie Y, Kennedy SM, et al.: Protection against Western diet-induced obesity and hepatic steatosis in liver fatty acid-binding protein knockout mice. Hepatology 2006, 44:1191–1205.

    Article  PubMed  CAS  Google Scholar 

  28. Binas B, Erol E: FABPs as determinants of myocellular and hepatic fuel metabolism. Mol Cell Biochem 2006, In press.

  29. Shearer J, Fueger PT, Bracy DP, et al.: Partial gene deletion of heart-type fatty acid-binding protein limits the severity of dietary-induced insulin resistance. Diabetes 2005, 54:3133–3139.

    Article  PubMed  CAS  Google Scholar 

  30. Weisberg SP, McCann D, Desai M, et al.: Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003, 112:1796–1808.

    Article  PubMed  CAS  Google Scholar 

  31. 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, 112:1821–1830.

    Article  PubMed  CAS  Google Scholar 

  32. Arkan MC, Hevener AL, Greten FR, et al.: IKK-beta links inflammation to obesity-induced insulin resistance. Nat Med 2005, 11:191–198.

    Article  PubMed  CAS  Google Scholar 

  33. Fu Y, Luo L, Luo N, Garvey WT: Lipid metabolism mediated by adipocyte lipid binding protein (ALBP/aP2) gene expression in human THP-1 macrophages. Atherosclerosis 2006, 188:102–111.

    Article  PubMed  CAS  Google Scholar 

  34. Adida A, Spener F: Adipocyte-type fatty acid-binding protein as inter-compartmental shuttle for peroxisome proliferator activated receptor gamma agonists in cultured cell. Biochim Biophys Acta 2006, 1761:172–181.

    PubMed  CAS  Google Scholar 

  35. Minokoshi Y, Kim YB, Peroni OD, et al.: Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 2002, 415:339–343.

    Article  PubMed  CAS  Google Scholar 

  36. 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, 55:1915–1922.

    Article  PubMed  CAS  Google Scholar 

  37. Desvergne B, Wahli W: Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr Rev 1999, 20:649–688.

    Article  PubMed  CAS  Google Scholar 

  38. Shen WJ, Liang Y, Hong R, et al.: Characterization of the functional interaction of adipocyte lipid-binding protein with hormone-sensitive lipase. J Biol Chem 2001, 276:49443–49448.

    Article  PubMed  CAS  Google Scholar 

  39. 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, 14:4445–4448.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  41. Gromova I, Gromov P, Wolf H, Celis JE: Protein abundancy and mRNA levels of the adipocyte-type fatty acid binding protein correlate in non-invasive and invasive bladder transitional cell carcinomas. Int J Oncol 1998, 13:379–383.

    PubMed  CAS  Google Scholar 

  42. Adamson J, Morgan EA, Beesley C, et al.: High-level expression of cutaneous fatty acid-binding protein in prostatic carcinomas and its effect on tumorigenicity. Oncogene 2003, 22:2739–2749.

    Article  PubMed  CAS  Google Scholar 

  43. Yang Y, Spitzer E, Kenney N, et al.: Members of the fatty acid binding protein family are differentiation factors for the mammary gland. J Cell Biol 1994, 127:1097–1109.

    Article  PubMed  CAS  Google Scholar 

  44. Naundorf H, Zschiesche W, Reszka R, Fichtner I: Influence of liposomes rich in unsaturated or saturated fatty acids on the growth of human xenotransplanted mammary carcinomas and on the levels of heart type fatty acid binding protein. In Vivo 1995, 9:247–251.

    PubMed  CAS  Google Scholar 

  45. Theocharis S, Margeli A, Vielh P, Kouraklis G: Peroxisome proliferator-activated receptor-gamma ligands as cell-cycle modulators. Cancer Treat Rev 2004, 30:545–554.

    Article  PubMed  CAS  Google Scholar 

  46. Daynes RA, Jones DC: Emerging roles of PPARs in inflammation and immunity. Nat Rev Immunol 2002, 2:748–759.

    Article  PubMed  CAS  Google Scholar 

  47. Murphy CT, McCarroll SA, Bargmann CI, et al.: Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. Nature 2003, 424:277–283.

    Article  PubMed  CAS  Google Scholar 

  48. Ha MK, Soo Cho J, Baik OR, et al.: Caenorhabditis elegans as a screening tool for the endothelial cell-derived putative aging-related proteins detected by proteomic analysis. Proteomics 2006, 6:3339–3351.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Genetics and Complex Diseases, Harvard School of Public Health, Building 1, 665 Huntington Avenue, Boston, MA, 02115, USA

    Gökhan S. Hotamisligil MD, PhD

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  1. Ebru Erbay MD, PhD
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  2. Haiming Cao PhD
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  3. Gökhan S. Hotamisligil MD, PhD
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Correspondence to Gökhan S. Hotamisligil MD, PhD.

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Erbay, E., Cao, H. & Hotamisligil, G.S. Adipocyte/macrophage fatty acid binding proteins in metabolic syndrome. Curr Atheroscler Rep 9, 222–229 (2007). https://doi.org/10.1007/s11883-007-0023-6

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