title: Capillary endothelial fatty acid binding proteins 4 and 5 play a critical role in fatty acid uptake in heart and skeletal muscle.
abstract: OBJECTIVE
  Fatty acids (FAs) are the major substrate for energy production in the heart. Here, we hypothesize that capillary endothelial fatty acid binding protein 4 (FABP4) and FABP5 play an important role in providing sufficient FAs to the myocardium.
  
  
  RESULTS
  Both FABP4/5 were abundantly expressed in capillary endothelium in the heart and skeletal muscle. The uptake of a FA analogue, 125I-15-(p-iodophenyl)-3-(R,S)-methyl pentadecanoic acid, was significantly reduced in these tissues in double-knockout (DKO) mice for FABP4/5 compared with wild-type mice. In contrast, the uptake of a glucose analogue, 18F-fluorodeoxyglucose, was remarkably increased in DKO mice. The expression of transcripts for the oxidative catabolism of FAs was reduced during fasting, whereas transcripts for the glycolytic pathway were not altered in DKO hearts. Notably, metabolome analysis revealed that phosphocreatine and ADP levels were significantly lower in DKO hearts, whereas ATP content was kept at a normal level. The protein expression levels of the glucose transporter Glut4 and the phosphorylated form of phosphofructokinase-2 were increased in DKO hearts, whereas the phosphorylation of insulin receptor-β and Akt was comparable between wild-type and DKO hearts during fasting, suggesting that a dramatic increase in glucose usage during fasting is insulin independent and is at least partly attributed to the post-transcriptional and allosteric regulation of key proteins that regulate glucose uptake and glycolysis.
  
  
  CONCLUSIONS
  Capillary endothelial FABP4/5 are required for FA transport into FA-consuming tissues that include the heart. These findings identify FABP4/5 as promising targets for controlling the metabolism of energy substrates in FA-consuming organs that have muscle-type continuous capillary.
authors: From the Department of Medicine and Biological Science (T.I., T.S., K.G., M.R.A.AS., H.M., M.A., M.K.), Education and Research Support Center (T.I., M.K.), Department of Bioimaging Information Analysis (H.H., A.Y.), and Department of Diagnostic Radiology and Nuclear Medicine (K.E.), Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan; Department of Genetics and Complex Diseases and Nutrition, Broad Institute of Harvard and MIT, Harvard School of Public Health, Boston, MA (K.M., G.S.H.); Department of Biochemistry (T.H., Y.N., M.S.), JST, ERATO, Suematsu Gas Biology Project (T.H., Y.N., M.S.), and Department of Cardiology (M.S.), Keio University School of Medicine, Tokyo, Japan; and Department of Medicine, Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO (N.A.A.). Current address for K.M.: Department of Complementary and Alternative Medicine, Graduate School of Medicine, Osaka University Hospital, Osaka, Japan. Current address for H.H.: Department of Molecular Imaging and Radiotherapy, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
authors: Tatsuya
authors: T
authors: Iso
authors: Kazuhisa
authors: K
authors: Maeda
authors: Hirofumi
authors: H
authors: Hanaoka
authors: Toshihiro
authors: T
authors: Suga
authors: Kosaku
authors: K
authors: Goto
authors: Mas Rizky A A
authors: MR
authors: Syamsunarno
authors: Takako
authors: T
authors: Hishiki
authors: Yoshiko
authors: Y
authors: Nagahata
authors: Hiroki
authors: H
authors: Matsui
authors: Masashi
authors: M
authors: Arai
authors: Aiko
authors: A
authors: Yamaguchi
authors: Nada A
authors: NA
authors: Abumrad
authors: Motoaki
authors: M
authors: Sano
authors: Makoto
authors: M
authors: Suematsu
authors: Keigo
authors: K
authors: Endo
authors: Gökhan S
authors: GS
authors: Hotamisligil
authors: Masahiko
authors: M
authors: Kurabayashi
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000818:Animals; D004730:Endothelium, Vascular / Q000378:metabolism; D004734:Energy Metabolism / Q000502:physiology*; D050556:Fatty Acid-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism* / Q000493:pharmacokinetics; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics; D007462:Iodobenzenes / Q000493:pharmacokinetics; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010725:Phosphocreatine / Q000378:metabolism; D025481:Phosphofructokinase-2 / Q000378:metabolism
chemical_list: C493411:Fabp4 protein, mouse; C082667:Fabp5 protein, mouse; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids; D007462:Iodobenzenes; D009363:Neoplasm Proteins; D010725:Phosphocreatine; C049338:iodofiltic acid; D019788:Fluorodeoxyglucose F18; D000244:Adenosine Diphosphate; D025481:Phosphofructokinase-2
keywords: capillaries; endothelial cells; fatty acid binding proteins; fatty acids; glucose; metabolism
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