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High Dietary Fat Exacerbates Weight Gain and Obesity in Female Liver Fatty Acid Binding Protein Gene-Ablated Mice

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Lipids

Abstract

Since liver fatty acid binding protein (L-FABP) facilitates uptake/oxidation of long-chain fatty acids in cultured transfected cells and primary hepatocytes, loss of L-FABP was expected to exacerbate weight gain and/or obesity in response to high dietary fat. Male and female wild-type (WT) and L-FABP gene-ablated mice, pair-fed a defined isocaloric control or high fat diet for 12 weeks, consumed equal amounts of food by weight and kcal. Male WT mice gained weight faster than their female WT counterparts regardless of diet. L-FABP gene ablation enhanced weight gain more in female than male mice—an effect exacerbated by high fat diet. Dual emission X-ray absorptiometry revealed high-fat fed male and female WT mice gained mostly fat tissue mass (FTM). L-FABP gene ablation increased FTM in female, but not male, mice—an effect also exacerbated by high fat diet. Concomitantly, L-FABP gene ablation decreased serum β-hydroxybutyrate in male and female mice fed the control diet and, even more so, on the high-fat diet. Thus, L-FABP gene ablation decreased fat oxidation and sensitized all mice to weight gain as whole body FTM and LTM—with the most gain observed in FTM of control vs high-fat fed female L-FABP null mice. Taken together, these results indicate loss of L-FABP exacerbates weight gain and/or obesity in response to high dietary fat.

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Abbreviations

L-FABP:

Liver fatty acid binding protein

FTM:

Fat tissue mass

LTM:

Lean tissue mass

WT:

Wild-type

DEXA:

Dual emission X-ray absorptiometry

LCFA:

Long chain fatty acids

rtPCR:

Real-time PCR

ACO-1:

Palmitoyl CoA oxidase-1

ACO-2:

Branched chain CoA oxidase-2

ACO-3:

Pristanoyl CoA oxidase-3

PBE:

L-peroxisomal bifunctional enzyme

CpT1-l:

Carnitine palmitoyl CoA acyltransferase-1

MCAD:

Mitochondrial medium chain acyl CoA dehydrogenase

HMG-CoA Syn:

HMG-CoA synthase

CYP4A3:

Cytochrome p450, family 4, subfamily A, polypeptide 3

References

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

    PubMed  CAS  Google Scholar 

  2. Richieri GV, Ogata RT, Kleinfeld AM (1994) Equilibrium constants for the binding of fatty acids with fatty acid binding proteins from adipocyte, intestine, heart and liver measured with the fluorescent probe ADIFAB. J Biol Chem 269:23918–23930

    PubMed  CAS  Google Scholar 

  3. Frolov A, Cho TH, Murphy EJ, Schroeder F (1997) Isoforms of rat liver fatty acid binding protein differ in structure and affinity for fatty acids and fatty acyl CoAs. Biochemistry 36:6545–6555

    Article  PubMed  CAS  Google Scholar 

  4. Thompson J, Ory J, Reese-Wagoner A, Banaszak L (1999) The liver fatty acid binding protein-comparison of cavity properties of intracellular lipid binding proteins. Mol Cell Biochem 192:9–16

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  6. He Y, Yang X, Wang H, Estephan R, Francis F, Kodukula S, Storch J, Stark RE (2007) Solution-state molecular structure of apo and oleate-liganded liver fatty acid binding protein. Biochemistry 46:12543–12556

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  8. Jolly CA, Wilton DA, Schroeder F (2000) Microsomal fatty acyl CoA transacylation and hydrolysis: fatty acyl CoA species dependent modulation by liver fatty acyl CoA binding proteins. Biochim Biophys Acta 1483:185–197

    PubMed  CAS  Google Scholar 

  9. Schroeder F, Jolly CA, Cho TH, Frolov AA (1998) Fatty acid binding protein isoforms: structure and function. Chem Phys Lipids 92:1–25

    Article  PubMed  CAS  Google Scholar 

  10. Chao H, Zhou M, McIntosh A, Schroeder F, Kier AB (2003) Acyl CoA binding protein and cholesterol differentially alter fatty acyl CoA utilization by microsomal acyl CoA: cholesterol transferase. J Lipid Res 44:72–83

    Article  PubMed  CAS  Google Scholar 

  11. Nemecz G, Schroeder F (1991) Selective binding of cholesterol by recombinant fatty acid-binding proteins. J Biol Chem 266:17180–17186

    PubMed  CAS  Google Scholar 

  12. Woldegiorgis G, Bremer J, Shrago E (1985) Substrate inhibition of carnitine palmitoyltransferase by palmitoyl-CoA and activation by phospholipids and proteins. Biochim Biophys Acta 837:135–140

    PubMed  CAS  Google Scholar 

  13. Bhuiyan AKMJ, Pande SV (1994) Carnitine palmitoyltransferase activities: effects of serum albumin, acyl-CoA binding protein and fatty acid binding protein. Mol Cell Biochem 139:109–116

    Article  PubMed  CAS  Google Scholar 

  14. Reubsaet FA, Veerkamp JH, Bruckwilder ML, Trijbels JM, Monnens LA (1990) The involvement of fatty acid-binding protein in peroxisomal fatty acid oxidation. FEBS Lett 267:229–230

    Article  PubMed  CAS  Google Scholar 

  15. Rasmussen JT, Faergeman NJ, Kristiansen K, Knudsen J (1994) Acyl-CoA-binding protein (ACBP) can mediate intermembrane acyl-CoA transport and donate acyl-CoA for beta-oxidation and glycerolipid synthesis. Biochem J 299:165–170

    PubMed  CAS  Google Scholar 

  16. Murphy EJ, Prows DR, Jefferson JR, Schroeder F (1996) Liver fatty acid binding protein expression in transfected fibroblasts stimulates fatty acid uptake and metabolism. Biochim Biophys Acta 1301:191–198

    PubMed  Google Scholar 

  17. Murphy EJ (1998) L-FABP and I-FABP expression increase NBD-stearate uptake and cytoplasmic diffusion in L-cells. Am J Physiol 275:G244–G249

    PubMed  CAS  Google Scholar 

  18. Prows DR, Murphy EJ, Schroeder F (1995) Intestinal and liver fatty acid binding proteins differentially affect fatty acid uptake and esterification in L-Cells. Lipids 30:907–910

    Article  PubMed  CAS  Google Scholar 

  19. Wolfrum C, Buhlman C, Rolf B, Borchers T, Spener F (1999) Variation of liver 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 1437:194–201

    PubMed  CAS  Google Scholar 

  20. Atshaves BP, Storey S, Huang H, Schroeder F (2004) Liver fatty acid binding protein expression enhances branched-chain fatty acid metabolism. Mol Cell Biochem 259:115–129

    Article  PubMed  CAS  Google Scholar 

  21. Jefferson JR, Slotte JP, Nemecz G, Pastuszyn A, Scallen TJ, Schroeder F (1991) Intracellular sterol distribution in transfected mouse L-cell fibroblasts expressing rat liver fatty acid binding protein. J Biol Chem 266:5486–5496

    PubMed  CAS  Google Scholar 

  22. Veerkamp JH, van Moerkerk HT (1993) Fatty acid-binding protein and its relation to fatty acid oxidation. Mol Cell Biochem 123:101–106

    Article  PubMed  CAS  Google Scholar 

  23. Veerkamp JH, van Moerkerk HT (1992) The fatty acid-binding protein content and fatty acid oxidation capacity of rat tissues. Prog Clin Biol Res 375:205–210

    PubMed  CAS  Google Scholar 

  24. Vanden Heuvel JP, Sterchele PF, Nesbit DJ, Peterson RE (1993) Coordinate induction of acyl-CoA binding protein, fatty acid binding protein and peroxisomal β-oxidation by peroxisome proliferators. Biochem. Biophys. Acta 1177:183–190

    Article  Google Scholar 

  25. Brandes R, Kaikaus RM, Lysenko N, Ockner RK, Bass NM (1990) Induction of fatty acid binding protein by peroxisome proliferators in primary hepatocyte cultures and its relationship to the induction of peroxisomal beta-oxidation. Biochim Biophys Acta 1034:53–61

    PubMed  CAS  Google Scholar 

  26. Martin GG, Danneberg H, Kumar LS, Atshaves BP, Erol E, Bader M, Schroeder F, Binas B (2003) Decreased liver fatty acid binding capacity and altered liver lipid distribution in mice lacking the liver fatty acid binding protein (L-FABP) gene. J Biol Chem 278:21429–21438

    Article  PubMed  CAS  Google Scholar 

  27. Martin GG, Huang H, Atshaves BP, Binas B, Schroeder F (2003) 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 42:11520–11532

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  29. Newberry EP, Xie Y, Kennedy S, Buhman KK, Luo J, Gross RW, Davidson NO (2003) 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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  31. Atshaves BP, McIntosh AL, Payne HR, Mackie J, Kier AB, Schroeder F (2005) Effect of branched-chain fatty acid on lipid dynamics in mice lacking liver fatty acid binding protein gene. Am J Physiol 288:C543–C558

    Article  CAS  Google Scholar 

  32. Thigpen JE, Setchell KD, Goelz MF, Forsythe DB (1999) The phyto estrogen content of rodent diets. Envron Health Persp 107:A182–A183

    Article  CAS  Google Scholar 

  33. Atshaves BP, McIntosh AL, Martin GG, Landrock D, Payne HR, Bhuvanendran S, Landrock K, Lyuksyutova OI, Johnson JD, Macfarlane RD, Kier AB, Schroeder F (2009) Overexpression of sterol carrier protein-2 differentially alters hepatic cholesterol accumulation in cholesterol-fed mice. J Lipid Res 50:1429–1447

    Article  PubMed  CAS  Google Scholar 

  34. Atshaves BP, Payne HR, McIntosh AL, Tichy SE, Russell D, Kier AB, Schroeder F (2004) Sexually dimorphic metabolism of branched chain lipids in C57BL/6J mice. J Lipid Res 45:812–830

    Article  PubMed  CAS  Google Scholar 

  35. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods 25:402–408

    Article  PubMed  CAS  Google Scholar 

  36. Powell GL, Tippett PS, Kiorpes TC, McMillin-Wood J, Coll KE, Schultz H, Tanaka K, Kang ES, Shrago E (1985) Fatty acyl CoA as an effector molecule in metabolism. Fed Proc 44:81–84

    Google Scholar 

  37. Gossett RE, Frolov AA, Roths JB, Behnke WD, Kier AB, Schroeder F (1996) Acyl CoA binding proteins: multiplicity and function. Lipids 31:895–918

    Article  PubMed  CAS  Google Scholar 

  38. Faergeman NJ, Knudsen J (1997) Role of long-chain fatty acyl-CoA esters in the regulation of metabolism and in cell signalling. Biochem J 323:1–12

    PubMed  CAS  Google Scholar 

  39. Huang H, Starodub O, McIntosh A, Kier AB, Schroeder F (2002) Liver fatty acid binding protein targets fatty acids to the nucleus: real-time confocal and multiphoton fluorescence imaging in living cells. J Biol Chem 277:29139–29151

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  41. Wang Y, Botolin D, Xu J, Christian B, Mitchell E, Jayaprakasam B, Nair M, Peters JM, Busik J, Olson LK, Jump DB (2006) Regulation of fatty acid elongase and desaturase expression in diabetes and obesity. J Lipid Res 47:2028–2041

    Article  PubMed  CAS  Google Scholar 

  42. Martin GG, Atshaves BP, McIntosh AL, Mackie JT, Kier AB, Schroeder F (2005) Liver fatty acid binding protein (L-FABP) gene ablation alters liver bile acid metabolism in male mice. Biochem J 391:549–560

    Article  PubMed  CAS  Google Scholar 

  43. Martin GG, Atshaves BP, McIntosh AL, Mackie JT, Kier AB, Schroeder F (2006) Liver fatty acid binding protein (L-FABP) gene ablation potentiates hepatic cholesterol accumulation in cholesterol-fed female mice. Am J Physiol 290:G36–G48

    CAS  Google Scholar 

  44. Martin GG, Atshaves BP, McIntosh AL, Mackie JT, Kier AB, Schroeder F (2008) Liver fatty acid binding protein gene ablated female mice exhibit increased age dependent obesity. J Nutr 138:1859–1865

    PubMed  CAS  Google Scholar 

  45. Martin GG, Atshaves BP, McIntosh AL, Mackie JT, Kier AB, Schroeder F (2009) Liver fatty acid binding protein gene ablation enhances age-dependent weight gain in male mice. Mol Cell Biochem 324:101–115

    Article  PubMed  CAS  Google Scholar 

  46. Newberry EP, Kennedy SM, Xie Y, Sternard BT, Luo J, Davidson NO (2008) 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

    Article  PubMed  CAS  Google Scholar 

  47. Newberry EP, Xie Y, Kennedy SM, Luo J, Davidson NO (2006) Protection against western diet-induced obesity and hepatic steatosis in liver fatty acid binding protein knockout mice. Hepatology 44:1191–1205

    Article  PubMed  CAS  Google Scholar 

  48. Pignon J-P, Bailey NC, Baraona E, Lieber CS (1987) Fatty acid-binding protein: a major contributor to the ethanol-induced increase in liver cytosolic proteins in the rat. Hepatology 7:865–871

    Article  PubMed  CAS  Google Scholar 

  49. Mackie JT, Atshaves BP, Payne HR, McIntosh AL, Schroeder F, Kier AB (2009) Phytol-induced hepatotoxicity in mice. Toxicol Pathol 37:201–208

    Article  PubMed  CAS  Google Scholar 

  50. Schroeder F, Petrescu AD, Huang H, Atshaves BP, McIntosh AL, Martin GG, Hostetler HA, Vespa A, Landrock K, Landrock D, Payne HR, Kier AB (2008) Role of fatty acid binding proteins and long chain fatty acids in modulating nuclear receptors and gene transcription. Lipids 43:1–17

    Article  PubMed  CAS  Google Scholar 

  51. McIntosh AL, Atshaves BP, Hostetler HA, Huang H, Davis J, Lyuksyutova OI, Landrock D, Kier AB, Schroeder F (2009) Liver type fatty acid binding protein (L-FABP) gene ablation reduces nuclear ligand distribution and peroxisome proliferator activated receptor-alpha activity in cultured primary hepatocytes. Arch Biochem Biophys 485:160–173

    Article  PubMed  CAS  Google Scholar 

  52. Djouadi F, Weinheimer CJ, Saffitz JE, Pitchford C, Bastin J, Gonzalez FJ (1998) A gender-related defect in lipid metabolism and glucose homeostasis in PPARalpha deficient mice. J Clin Inv 102:1083–1091

    Article  CAS  Google Scholar 

  53. Rosenberger TA, Hovda JT, Peters JM (2002) Targeted disruption of peroxisome proliferator activated receptor beta (delta) results in distinct gender differences in mouse brain phospholipid and esterified fatty acid levels. Lipids 37:495–500

    Article  PubMed  CAS  Google Scholar 

  54. Martin GG, Atshaves BP, Huang H, McIntosh AL, Williams BW, Russell DH, Kier AB and Schroeder F (2009) Hepatic phenotype of liver fatty acid binding protein (L-FABP) gene ablated mice. Am J Physiol (submitted)

  55. Hostetler HA, Petrescu AD, Kier AB, Schroeder F (2005) Peroxisome proliferator activated receptor alpha (PPARalpha) interacts with high affinity and is conformationally responsive to endogenous ligands. J Biol Chem 280:18667–18682

    Article  PubMed  CAS  Google Scholar 

  56. Hostetler HA, Kier AB, Schroeder F (2006) Very-long-chain and branched-chain fatty acyl CoAs are high affinity ligands for the peroxisome proliferator-activated receptor alpha (PPARalpha). Biochemistry 45:7669–7681

    Article  PubMed  CAS  Google Scholar 

  57. Tallman DL, Noto AD, Taylor CG (2009) Low and high fat diets inconsistently induce obesity in C57BL/6J mice and obesity compromises n-3 fatty acid status. Lipids 44:577–580

    Article  PubMed  CAS  Google Scholar 

  58. Koza RA, Nikonova L, Hogan J, Rim JS, Mendoza T, Faulk C, Skaf J, Kozak LP (2006) Changes in gene expression foreshadow diet-induced obesity in genetically identical mice. PLoS Genet 2:e81

    Article  PubMed  CAS  Google Scholar 

  59. Burcelin R, Crivelli V, Dacosta A, Roy-Tirelli A, Thorens B (2002) Heterogeneous metabolic adaptation of C57BL/6J mice to high fat diet. Am J Physiol Endocrinol Metab 282:E834–E842

    PubMed  CAS  Google Scholar 

  60. Bogdanov AM, Mishin AS, Yampolsky IV, Belousov VV, Chudakov DM, Subach FV, Verkhusha VV, Lukyanov S, Lukyonov KA (2009) Green fluorescent proteins are light-induced electron donors. Nat Chem Biol 5:459–461. doi:10.1038/nchembio.174

    Article  PubMed  CAS  Google Scholar 

  61. Luxon BA, Weisiger RA (1993) Sex differences in intracellular fatty acid transport: role of cytoplasmic binding proteins. Am J Physiol 265:G831–G841

    PubMed  CAS  Google Scholar 

  62. Weisiger RA (2005) Cytosolic fatty acid binding proteins catalyze two distinct steps in intracellular transport of their ligands. Mol Cell Biochem 239:35–42

    Article  Google Scholar 

  63. Hotamisligl GS, Johnson RS, Distel RJ, Ellis RF, Papaioannou VE, Spiegelman BM (1996) Uncoupling of obesity from insulin resistance through a targeted mutation in aP2, the adipocyte fatty acid binding protein. Science 274:1377–1379

    Article  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported in part by the United States Public Health Service National Institutes of Health grants DK41402 (FS and ABK), GM31651 (FS and ABK), and DK70965 (BPA).

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Authors and Affiliations

  1. Department of Physiology and Pharmacology, Texas A&M University, TVMC, College Station, TX, 77843-4466, USA

    Barbara P. Atshaves, Avery L. McIntosh, Stephen M. Storey, Kerstin K. Landrock & Friedhelm Schroeder

  2. Department of Pathobiology, Texas A&M University, TVMC, College Station, TX, 77843, USA

    Ann B. Kier

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  1. Barbara P. Atshaves
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  2. Avery L. McIntosh
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  5. Ann B. Kier
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  6. Friedhelm Schroeder
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Correspondence to Friedhelm Schroeder.

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Atshaves, B.P., McIntosh, A.L., Storey, S.M. et al. High Dietary Fat Exacerbates Weight Gain and Obesity in Female Liver Fatty Acid Binding Protein Gene-Ablated Mice. Lipids 45, 97–110 (2010). https://doi.org/10.1007/s11745-009-3379-2

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