title: Acute regulation of cardiac metabolism by the hexosamine biosynthesis pathway and protein O-GlcNAcylation.
abstract: OBJECTIVE
  The hexosamine biosynthesis pathway (HBP) flux and protein O-linked N-acetyl-glucosamine (O-GlcNAc) levels have been implicated in mediating the adverse effects of diabetes in the cardiovascular system. Activation of these pathways with glucosamine has been shown to mimic some of the diabetes-induced functional and structural changes in the heart; however, the effect on cardiac metabolism is not known. Therefore, the primary goal of this study was to determine the effects of glucosamine on cardiac substrate utilization.
  
  
  METHODS
  Isolated rat hearts were perfused with glucosamine (0-10 mM) to increase HBP flux under normoxic conditions. Metabolic fluxes were determined by (13)C-NMR isotopomer analysis; UDP-GlcNAc a precursor of O-GlcNAc synthesis was assessed by HPLC and immunoblot analysis was used to determine O-GlcNAc levels, phospho- and total levels of AMPK and ACC, and membrane levels of FAT/CD36.
  
  
  RESULTS
  Glucosamine caused a dose dependent increase in both UDP-GlcNAc and O-GlcNAc levels, which was associated with a significant increase in palmitate oxidation with a concomitant decrease in lactate and pyruvate oxidation. There was no effect of glucosamine on AMPK or ACC phosphorylation; however, membrane levels of the fatty acid transport protein FAT/CD36 were increased and preliminary studies suggest that FAT/CD36 is a potential target for O-GlcNAcylation.
  
  
  CONCLUSIONS
  These data demonstrate that acute modulation of HBP and protein O-GlcNAcylation in the heart stimulates fatty acid oxidation, possibly by increasing plasma membrane levels of FAT/CD36, raising the intriguing possibility that the HBP and O-GlcNAc turnover represent a novel, glucose dependent mechanism for regulating cardiac metabolism.
authors.affiliation: Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Boglárka
authors.initials: B
authors.lastname: Laczy
authors.forename: Norbert
authors.initials: N
authors.lastname: Fülöp
authors.forename: Arzu
authors.initials: A
authors.lastname: Onay-Besikci
authors.forename: Christine
authors.initials: C
authors.lastname: Des Rosiers
authors.forename: John C
authors.initials: JC
authors.lastname: Chatham
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000117:Acetylglucosamine / Q000378:metabolism*; D000818:Animals; D053898:Biosynthetic Pathways; D018955:CD36 Antigens / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D006031:Glycosylation; D006334:Heart Function Tests; D015151:Immunoblotting; D066298:In Vitro Techniques; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction; D010477:Perfusion; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013379:Substrate Specificity; D014537:Uridine Diphosphate N-Acetylglucosamine / Q000378:metabolism
chemical_list: D018955:CD36 Antigens; C008132:Cd36 protein, rat; D011506:Proteins; D014537:Uridine Diphosphate N-Acetylglucosamine; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D000117:Acetylglucosamine