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FABPs as determinants of myocellular and hepatic fuel metabolism

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Abstract

In vitro experiments and expression patterns have long suggested important roles for the genetically related cytosolic fatty acid binding proteins (FABPs) in lipid metabolism. However, evidence for such roles in vivo has become available only recently from genetic manipulation of FABP expression in mice. Here, we summarize the fuel-metabolic phenotypes of mice lacking the genes encoding heart-type FABP (H−/− mice) or liver-type FABP (L−/− mice). Cytosolic extracts from H−/− heart and skeletal muscle and from L−/− liver showed massively reduced binding of long chain fatty acids (LCFA) and, in case of L−/− liver, also of LCFA-CoA. Uptake, oxidation, and esterification LCFA, when measured in vivo and/or ex vivo, were markedly reduced in H−/− heart and muscle and in L−/− liver. The reduced LCFA oxidation in H−/− heart and L−/− liver was not due to reduced activity of PPARa, a fatty acid-sensitive transcription factor that determines the lipid-oxidative capacity in these organs. In H−/− mice, mechanisms of compensation were partially studied and included a redistribution of muscle mitochondria as well as increases of cardiac and skeletal muscle glucose uptakes and of hepatic ketogenesis. In skeletal muscle, the altered glucose uptake included decreased basal but increased insulin-dependent components. Metabolic compensation was only partial, however, since the H−/− mice showed decreased exercise tolerance. In conclusion, the recent studies established H- and L-FABP as major determinants of regional LCFA utilization; therefore the H−/− and L−/− mice are attractive models for studying principles of fuel selection and metabolic homeostasis.

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References

  1. Atshaves BP, McIntosh AM, Lyuksyutova OI, Zipfel W, Webb WW, Schroeder F: Liver fatty acid-binding protein gene ablation inhibits branched-chain fatty acid metabolism in cultured primary hepatocytes. J Biol Chem 279(30): 30954–30965, 2004

    Article  PubMed  CAS  Google Scholar 

  2. Bastie CC, Hajri T, Drover VA, Grimaldi PA, Abumrad NA: CD36 in myocytes channels fatty acids to a lipase-accessible triglyceride pool that is related to cell lipid and insulin responsiveness. Diabetes 53(9): 2209–2216, 2004

    Article  PubMed  CAS  Google Scholar 

  3. Binas B, Gusterson B, Wallace R, Clark AJ: Epithelial proliferation and differentiation in the mammary gland do not correlate with cFABP gene expression during early pregnancy. Dev Genet 17(2): 167–175, 1995

    Article  PubMed  CAS  Google Scholar 

  4. Binas B, Danneberg H, McWhir J, Mullins L, Clark AJ: Requirement for the heart-type fatty acid binding protein in cardiac fatty acid utilization. FASEB J 13(8): 805–812, 1999

    PubMed  CAS  Google Scholar 

  5. Binas B, Han XX, Erol E, Luiken JJ, Glatz JF, Dyck DJ, Motazavi R, Adihetty PJ, Hood DA, Bonen A: A null mutation in H-FABP only partially inhibits skeletal muscle fatty acid metabolism. Am J Physiol Endocrinol Metab 285(3): E481–E489, 2003

    PubMed  CAS  Google Scholar 

  6. Brouillette C, Bosse Y, Perusse L, Gaudet D, Vohl MC: Effect of liver fatty acid binding protein (FABP) T94A missense mutation on plasma lipoprotein responsiveness to treatment with fenofibrate. J Hum Genet 49(8): 424–432, 2004

    Article  PubMed  CAS  Google Scholar 

  7. Cheng L, Ding G, Qin Q, Huang Y, Lewis W, He N, Evans RM, Schneider MD, Brako FA, Xiao Y, Chen YE, Yang Q: Cardiomyocyte-restricted peroxisome proliferator-activated receptor-delta deletion perturbs myocardial fatty acid oxidation and leads to cardiomyopathy. Nat Med. Oct 10 [Epub ahead of print], 2004

  8. Coburn CT, Knapp FF Jr, Febbraio M, Beets AL, Silverstein RL, Abumrad NA: Defective uptake and utilization of long chain fatty acids in muscle and adipose tissues of CD36 knockout mice. J Biol Chem 275(42): 32523–32529, 2000

    Article  PubMed  CAS  Google Scholar 

  9. Daniele N, Bordet JC, Mithieux G: Unsaturated fatty acids associated with glycogen may inhibit glucose-6 phosphatase in rat liver. J Nutr 127(12): 2289–2292, 1997

    PubMed  CAS  Google Scholar 

  10. Depre C, Vanoverschelde JL, Taegtmeyer H: Glucose for the heart. Circulation 99(4): 578–588, 1999

    PubMed  CAS  Google Scholar 

  11. Erol E, Kumar LS, Cline GW, Shulman GI, Kelly DP, Binas B: Liver fatty acid binding protein is required for high rates of hepatic fatty acid oxidation but not for the action of PPARalpha in fasting mice. FASEB J 18(2): 347–349, 2004

    PubMed  CAS  Google Scholar 

  12. Erol E, Cline GW, Kim JK, Taegtmeyer H, Binas B: Nonacute effects of H-FABP deficiency on skeletal muscle glucose uptake in vitro. Am J Physiol Endocrinol Metab 287(5): E977–E982, 2004

    Article  PubMed  CAS  Google Scholar 

  13. Glatz JF, Storch J: Unravelling the significance of cellular fatty acid-binding proteins. Curr Opin Lipidol 12(3): 267–274, 2001

    Article  PubMed  CAS  Google Scholar 

  14. Glatz JF, Schaap FG, Binas B, Bonen A, van der Vusse GJ, Luiken JJ: Cytoplasmic fatty acid-binding protein facilitates fatty acid utilization by skeletal muscle. Acta Physiol Scand 178(4): 367–371, 2003

    Article  PubMed  CAS  Google Scholar 

  15. Hanhoff T, Lucke C, Spener F: Insights into binding of fatty acids by fatty acid binding proteins. Mol Cell Biochem 239(1–2): 45–54, 2002

    Article  PubMed  CAS  Google Scholar 

  16. Hamilton JA: Fatty acid interactions with proteins: what X-ray crystal and NMR solution structures tell us. Prog Lipid Res 43(3): 177–199, 2004

    Article  PubMed  CAS  Google Scholar 

  17. Haunerland NH, Spener F: Fatty acid-binding proteins–insights from genetic manipulations. Prog Lipid Res 43(4): 328–349, 2004

    Article  PubMed  CAS  Google Scholar 

  18. Hertzel AV, Bernlohr DA: The mammalian fatty acid-binding protein multigene family: molecular and genetic insights into function. Trends Endocrinol Metab 11(5): 175–180, 2000

    Article  PubMed  CAS  Google Scholar 

  19. 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 43(12): 2105–2111, 2002

    Article  PubMed  CAS  Google Scholar 

  20. 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 274(5291): 1377–1379, 1996

    Article  PubMed  CAS  Google Scholar 

  21. Huang H, Starodub O, McIntosh A, Atshaves BP, Woldegiorgis G, Kier AB, Schroeder F: Liver fatty acid-binding protein colocalizes with peroxisome proliferator activated receptor alpha and enhances ligand distribution to nuclei of living cells. Biochemistry 43(9): 2484–2500, 2004

    Article  PubMed  CAS  Google Scholar 

  22. Johnson RS, Sheng M, Greenberg ME, Kolodner RD, Papaioannou VE, Spiegelman BM: Targeting of nonexpressed genes in embryonic stem cells via homologous recombination. Science 245(4923): 1234–1236, 1989

    Article  PubMed  CAS  Google Scholar 

  23. Jolly CA, Hubbell T, Behnke WD, Schroeder F: Fatty acid binding protein: stimulation of microsomal phosphatidic acid formation. Arch Biochem Biophys 341(1): 112–121, 1997

    Article  PubMed  CAS  Google Scholar 

  24. Kersten S, Seydoux J, Peters JM, Gonzalez FJ, Desvergne B, Wahli W: Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting. J Clin Invest 103(11): 1489–1498, 1999

    Article  PubMed  CAS  Google Scholar 

  25. Kim JK, Gimeno RE, Higashimori T, Kim HJ, Choi H, Punreddy S, Mozell RL, Tan G, Stricker-Krongrad A, Hirsch DJ, Fillmore JJ, Liu ZX, Dong J, Cline G, Stahl A, Lodish HF, Shulman GI: Inactivation of fatty acid transport protein 1 prevents fat-induced insulin resistance in skeletal muscle. J Clin Invest 113(5): 756–763, 2004

    Article  PubMed  CAS  Google Scholar 

  26. Koonen DP, Coumans WA, Arumugam Y, Bonen A, Glatz JF, Luiken JJ: Giant membrane vesicles as a model to study cellular substrate uptake dissected from metabolism. Mol Cell Biochem 239(1–2): 121–130, 2002

    Article  PubMed  CAS  Google Scholar 

  27. Lam TK, Carpentier A, Lewis GF, van de Werve G, Fantus IG, Giacca A: Mechanisms of the free fatty acid-induced increase in hepatic glucose production. Am J Physiol Endocrinol Metab 284(5): E863–E873, 2003

    PubMed  CAS  Google Scholar 

  28. LaLonde JM, Bernlohr DA, Banaszak LJ: The up-and-down beta-barrel proteins. FASEB J 8(15): 1240–1247, 1994

    PubMed  CAS  Google Scholar 

  29. Lehmann F, Haile S, Axen E, Medina C, Uppenberg J, Svensson S, Lundback T, Rondahl L, Barf T: Discovery of inhibitors of human adipocyte fatty acid-binding protein, a potential type 2 diabetes target. Bioorg Med Chem Lett 14(17): 4445–4448, 2004

    Article  PubMed  CAS  Google Scholar 

  30. Leone TC, Weinheimer CJ, Kelly DP: A critical role for the peroxisome proliferator-activated receptor alpha (PPARalpha) in the cellular fasting response: the PPARalpha-null mouse as a model of fatty acid oxidation disorders. Proc Natl Acad Sci USA 96(13): 7473–7478, 1999

    Article  PubMed  CAS  Google Scholar 

  31. Le May C, Pineau T, Bigot K, Kohl C, Girard J, Pegorier JP: Reduced hepatic fatty acid oxidation in fasting PPARalpha null mice is due to impaired mitochondrial hydroxymethylglutaryl-CoA synthase gene expression. FEBS Lett 475(3): 163–166, 2000

    Article  PubMed  CAS  Google Scholar 

  32. Luiken JJ, Koonen DP, Coumans WA, Pelsers MM, Binas B, Bonen A, Glatz JF: Long-chain fatty acid uptake by skeletal muscle is impaired in homozygous, but not heterozygous, heart-type-FABP null mice. Lipids 38(4): 491–496, 2003

    Article  PubMed  CAS  Google Scholar 

  33. Luxon BA, Milliano MT: Cytoplasmic codiffusion of fatty acids is not specific for fatty acid binding protein. Am J Physiol 273(3 Pt 1): C859–C867, 1997

    PubMed  CAS  Google Scholar 

  34. Maeda K, Uysal KT, Makowski L, Gorgun CZ, Atsumi G, Parker RA, Bruning J, Hertzel AV, Bernlohr DA, Hotamisligil GS: Role of the fatty acid binding protein mal1 in obesity and insulin resistance. Diabetes 52(2): 300–307, 2003

    Article  PubMed  CAS  Google Scholar 

  35. Makowski L, Hotamisligil GS: Fatty acid binding proteins–the evolutionary crossroads of inflammatory and metabolic responses. J Nutr 134(9): 2464S–2468S, 2004

    PubMed  CAS  Google Scholar 

  36. Martin GG, Danneberg H, Kumar LS, Atshaves BP, Erol E, Bader M, Schroeder F, Binas B: 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(24): 21429–21438, 2003

    Article  PubMed  CAS  Google Scholar 

  37. Martin GG, Huang H, Atshaves BP, Binas B, Schroeder F: Ablation of the liver fatty acid binding protein gene decreases fatty acyl CoA binding capacity and alters fatty acyl CoA pool distribution in mouse liver. Biochemistry 42(39): 11520–11532, 2003

    Article  PubMed  CAS  Google Scholar 

  38. McArthur MJ, Atshaves BP, Frolov A, Foxworth WD, Kier AB, Schroeder F: Cellular uptake and intracellular trafficking of long chain fatty acids. J Lipid Res 40(8): 1371–1383, 1999

    PubMed  CAS  Google Scholar 

  39. Mishkin S, Stein L, Gatmaitan Z, Arias IM: The binding of fatty acids to cytoplasmic proteins: binding to Z protein in liver and other tissues of the rat. Biochem Biophys Res Commun 47(5): 997–1003, 1972

    Article  PubMed  CAS  Google Scholar 

  40. Murphy EJ, Barcelo-Coblijn G, Binas B, Glatz JF: Heart fatty acid uptake is decreased in heart fatty acid-binding protein gene-ablated mice. J Biol Chem 279(33): 34481–34488, 2004

    Article  PubMed  CAS  Google Scholar 

  41. Newberry EP, Xie Y, Kennedy S, Han X, Buhman KK, Luo J, Gross RW, Davidson NO: 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(51): 51664–51672, 2003

    Article  PubMed  CAS  Google Scholar 

  42. Nikawa J, Tanabe T, Ogiwara H, Shiba T, Numa S: Inhibitory effects of long-chain acyl coenzyme A analogues on rat liver acetyl coenzyme A carboxylase. FEBS Lett 102(2): 223–226, 1979

    Article  PubMed  CAS  Google Scholar 

  43. 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 177(43): 56–58, 1972

    Article  PubMed  CAS  Google Scholar 

  44. Owada Y, Suzuki I, Noda T, Kondo H: Analysis on the phenotype of E-FABP-gene knockout mice. Mol Cell Biochem 239(1–2): 83–86, 2002

    Article  PubMed  CAS  Google Scholar 

  45. Pohl J, Ring A, Ehehalt R, Herrmann T, Stremmel W: New concepts of cellular fatty acid uptake: role of fatty acid transport proteins and of caveolae. Proc Nutr Soc 63(2): 259–2562, 2004

    Article  PubMed  CAS  Google Scholar 

  46. Randle PJ: Regulatory interactions between lipids and carbohydrates: the glucose fatty acid cycle after 35 years. Diabetes Metab Rev 14(4): 263–283, 1998

    Article  PubMed  CAS  Google Scholar 

  47. Samuel VT, Liu ZX, Qu X, Elder BD, Bilz S, Befroy D, Romanelli AJ, Shulman GI: Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J Biol Chem 279(31): 32345–32353, 2004

    Article  PubMed  CAS  Google Scholar 

  48. Schaap FG, Binas B, Danneberg H, van der Vusse GJ, Glatz JF: Impaired long-chain fatty acid utilization by cardiac myocytes isolated from mice lacking the heart-type fatty acid binding protein gene. Circ Res 85(4): 329–337, 1999

    PubMed  CAS  Google Scholar 

  49. Schaap FG, van der Vusse GJ, Glatz JF: Evolution of the family of intracellular lipid binding proteins in vertebrates. Mol Cell Biochem 239(1–2): 69–77, 2002

    Article  PubMed  CAS  Google Scholar 

  50. Schrauwen P, Hoeks J, Schaart G, Kornips E, Binas B, Van De Vusse GJ, Van Bilsen M, Luiken JJ, Coort SL, Glatz JF, Saris WH, Hesselink MK: Uncoupling protein 3 as a mitochondrial fatty acid anion exporter. FASEB J 17(15): 2272–2274, 2003

    PubMed  CAS  Google Scholar 

  51. Shearer J, Fueger PT, Rottman JN, Bracy DP, Binas B, Wasserman DH: Heart-Type Fatty Acid Binding Protein Reciprocally Regulates Glucose and Fatty Acid Utilization during Exercise. Am J Physiol Endocrinol Metab. Sep 28 [Epub ahead of print], 2004

  52. Shearer J, Fueger PT, Bracy DP, Rottman JN, Wasserman DH: Reduced Muscle-Type Fatty Acid Binding Protein (FABP) Protects Against Diet-Induced Insulin Resistance. Diabetes 53: A337, 2004

  53. Shulman GI: Unraveling the cellular mechanism of insulin resistance in humans: new insights from magnetic resonance spectroscopy. Physiology (Bethesda) 19: 183–190, 2004

    CAS  Google Scholar 

  54. Stewart JM, Blakely JA: Long chain fatty acids inhibit and medium chain fatty acids activate mammalian cardiac hexokinase. Biochim Biophys Acta 12;1484(2–3): 278–286, 2000

    Google Scholar 

  55. Storch J, Thumser AE: The fatty acid transport function of fatty acid-binding proteins. Biochim Biophys Acta 1486(1): 28–44, 2000

    PubMed  CAS  Google Scholar 

  56. Tan NS, Shaw NS, Vinckenbosch N, Liu P, Yasmin R, Desvergne B, Wahli W, Noy N: Selective cooperation between fatty acid binding proteins and peroxisome proliferator-activated receptors in regulating transcription. Mol Cell Biol 22(14): 5114–5127, 2002

    Article  PubMed  CAS  Google Scholar 

  57. Tippett PS, Neet KE: Specific inhibition of glucokinase by long chain acyl coenzymes A below the critical micelle concentration. J Biol Chem 257(21): 12839–12845, 1982

    PubMed  CAS  Google Scholar 

  58. Unger RH: Minireview: weapons of lean body mass destruction: the role of ectopic lipids in the metabolic syndrome. Endocrinology 144(12): 5159–5165, 2003

    Article  PubMed  CAS  Google Scholar 

  59. Vassileva G, Huwyler L, Poirier K, Agellon LB, Toth MJ: The intestinal fatty acid binding protein is not essential for dietary fat absorption in mice. FASEB J 14(13): 2040–2046, 2000

    Article  PubMed  CAS  Google Scholar 

  60. Veech RL: A humble hexose monophosphate pathway metabolite regulates short- and long-term control of lipogenesis. Proc Natl Acad Sci USA 100(10): 5578–5580, 2003

    Article  PubMed  CAS  Google Scholar 

  61. Watanabe K, Fujii H, Takahashi T, Kodama M, Aizawa Y, Ohta Y, Ono T, Hasegawa G, Naito M, Nakajima T, Kamijo Y, Gonzalez FJ, Aoyama T: Constitutive regulation of cardiac fatty acid metabolism through peroxisome proliferator-activated receptor alpha associated with age-dependent cardiac toxicity. J Biol Chem 275(29): 22293–22299, 2000

    Article  PubMed  CAS  Google Scholar 

  62. Weiss EP, Brown MD, Shuldiner AR, Hagberg JM: Fatty acid binding protein-2 gene variants and insulin resistance: gene and gene-environment interaction effects. Physiol Genomics 10: 145–157, 2002

    PubMed  CAS  Google Scholar 

  63. Wolfrum C, Buhlmann C, Rolf B, Borchers T, Spener F: Variation of liver-type fatty acid binding protein content in the human hepatoma cell line HepG2 by peroxisome proliferators and antisense RNA affects the rate of fatty acid uptake. Biochim Biophys Acta 1437(2): 194–201, 1999

    PubMed  CAS  Google Scholar 

  64. Wolfrum C, Borrmann CM, Borchers T, Spener F: Fatty acids and hypolipidemic drugs regulate peroxisome proliferator-activated receptors alpha – and gamma-mediated gene expression via liver fatty acid binding protein: a signaling path to the nucleus. Proc Natl Acad Sci USA 98(5): 2323–2328, 2001

    Article  PubMed  CAS  Google Scholar 

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Binas, B., Erol, E. FABPs as determinants of myocellular and hepatic fuel metabolism. Mol Cell Biochem 299, 75–84 (2007). https://doi.org/10.1007/s11010-005-9043-0

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