title: The p65 subunit of NF-kappaB binds to PGC-1alpha, linking inflammation and metabolic disturbances in cardiac cells.
abstract: OBJECTIVE
  Nuclear factor-kappaB (NF-kappaB) is a transcription factor induced by a wide range of stimuli, including hyperglycaemia and pro-inflammatory cytokines. It is associated with cardiac hypertrophy and heart failure. It was previously reported that the NF-kappaB-mediated inhibition of proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) might explain the shift in glucose metabolism during cardiac pathological processes induced by pro-inflammatory stimuli, although the specific mechanisms remain to be elucidated. We addressed the specific mechanisms by which exposure to tumour necrosis factor-alpha (TNF-alpha) results in PGC-1alpha down-regulation in cardiac cells and, as a consequence, in the metabolic dysregulation that underlies heart dysfunction and failure.
  
  
  RESULTS
  By using coimmunoprecipitation studies, we report for the first time that the p65 subunit of NF-kappaB is constitutively bound to PGC-1alpha in human cardiac cells and also in mouse heart, and that NF-kappaB activation by TNF-alpha exposure increases this binding. Overexpression and gene silencing analyses demonstrated that the main factor limiting the degree of this association is p65, because only the modulation of this protein modified the physical interaction. Our data show that the increased physical interaction between p65 and PGC-1alpha after NF-kappaB activation is responsible for the reduction in PGC-1alpha expression and subsequent dysregulation of glucose oxidation.
  
  
  CONCLUSIONS
  On the basis of these data, we propose that p65 directly represses PGC-1alpha activity in cardiac cells, thereby leading to a reduction in pyruvate dehydrogenase kinase 4 (PDK4) expression and the subsequent increase in glucose oxidation observed during the proinflammatory state.
authors.affiliation: Department of Pharmacology and Therapeutic Chemistry, IBUB (Institut de Biomedicina de Universitat de Barcelona)-Instituto de Salud Carlos III, Faculty of Pharmacy, University of Barcelona, Diagonal 643, Barcelona E-08028, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Alvarez-Guardia
authors.forename: Xavier
authors.initials: X
authors.lastname: Palomer
authors.forename: Teresa
authors.initials: T
authors.lastname: Coll
authors.forename: Mercy M
authors.initials: MM
authors.lastname: Davidson
authors.forename: Tung O
authors.initials: TO
authors.lastname: Chan
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Feldman
authors.forename: Juan C
authors.initials: JC
authors.lastname: Laguna
authors.forename: Manuel
authors.initials: M
authors.lastname: Vázquez-Carrera
mesh_terms: D000818:Animals; D002460:Cell Line; D004734:Energy Metabolism; D005947:Glucose / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D047468:Immunoprecipitation; D007249:Inflammation / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000276:immunology* / Q000378:metabolism; D010084:Oxidation-Reduction; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D011494:Protein Kinases / Q000378:metabolism; D034622:RNA Interference; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D006360:Heat-Shock Proteins; D018836:Inflammation Mediators; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C498143:RELA protein, human; C498144:Rela protein, mouse; D015534:Trans-Activators; D051996:Transcription Factor RelA; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D011494:Protein Kinases; C403287:pyruvate dehydrogenase kinase 4; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; D005947:Glucose