title: TNF-alpha reduces PGC-1alpha expression through NF-kappaB and p38 MAPK leading to increased glucose oxidation in a human cardiac cell model.
abstract: OBJECTIVE
  Inflammatory responses in the heart that are driven by sustained increases in cytokines have been associated with several pathological processes, including cardiac hypertrophy and heart failure. Emerging data suggest a link between cardiomyopathy and myocardial metabolism dysregulation. To further elucidate the relationship between a pro-inflammatory profile and cardiac metabolism dysregulation, a human cell line of cardiac origin, AC16, was treated with tumour necrosis factor-alpha (TNF-alpha).
  
  
  RESULTS
  Exposure of AC16 cells to TNF-alpha inhibited the expression of peroxisome proliferator-activated receptor coactivator 1alpha (PGC-1alpha), an upstream regulator of lipid and glucose oxidative metabolism. Studies performed with cardiac-specific transgenic mice (Mus musculus) overexpressing TNF-alpha, which have been well characterized as a model of cytokine-induced cardiomyopathy, also displayed reduced PGC-1alpha expression in the heart compared with that of control mice. The mechanism by which TNF-alpha reduced PGC-1alpha expression in vitro appeared to be largely mediated via both p38 mitogen-activated protein kinase and nuclear factor-kappaB pathways. PGC-1alpha downregulation resulted in an increase in glucose oxidation rate, which involved a reduction in pyruvate dehydrogenase kinase 4 expression and depended on the DNA-binding activity of both peroxisome proliferator-activated receptor beta/delta and estrogen-related receptor alpha transcription factors.
  
  
  CONCLUSIONS
  These results point to PGC-1alpha downregulation as a potential contributor to cardiac dysfunction and heart failure in metabolic disorders with an inflammatory background.
authors.affiliation: Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry, IBUB and CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)-Instituto de Salud Carlos III, Faculty of Pharmacy, University of Barcelona, Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Palomer
authors.forename: David
authors.initials: D
authors.lastname: Alvarez-Guardia
authors.forename: Ricardo
authors.initials: R
authors.lastname: Rodríguez-Calvo
authors.forename: Teresa
authors.initials: T
authors.lastname: Coll
authors.forename: Juan C
authors.initials: JC
authors.lastname: Laguna
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: Manuel
authors.initials: M
authors.lastname: Vázquez-Carrera
mesh_terms: D000818:Animals; D002460:Cell Line; D015536:Down-Regulation; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000276:immunology*; D016328:NF-kappa B / Q000378:metabolism*; D010084:Oxidation-Reduction; D047494:PPAR delta / Q000378:metabolism; D048068:PPAR-beta / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D047628:Estrogen Receptor alpha; D006360:Heat-Shock Proteins; D016328:NF-kappa B; D047494:PPAR delta; D048068:PPAR-beta; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D015534:Trans-Activators; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D005947:Glucose