title: Cardiac Myocyte KLF5 Regulates Ppara Expression and Cardiac Function.
abstract: BACKGROUND
  Fatty acid oxidation is transcriptionally regulated by peroxisome proliferator-activated receptor (PPAR)α and under normal conditions accounts for 70% of cardiac ATP content. Reduced Ppara expression during sepsis and heart failure leads to reduced fatty acid oxidation and myocardial energy deficiency. Many of the transcriptional regulators of Ppara are unknown.
  
  
  OBJECTIVE
  To determine the role of Krüppel-like factor 5 (KLF5) in transcriptional regulation of Ppara.
  
  
  RESULTS
  We discovered that KLF5 activates Ppara gene expression via direct promoter binding. This is blocked in hearts of septic mice by c-Jun, which binds an overlapping site on the Ppara promoter and reduces transcription. We generated cardiac myocyte-specific Klf5 knockout mice that showed reduced expression of cardiac Ppara and its downstream fatty acid metabolism-related targets. These changes were associated with reduced cardiac fatty acid oxidation, ATP levels, increased triglyceride accumulation, and cardiac dysfunction. Diabetic mice showed parallel changes in cardiac Klf5 and Ppara expression levels.
  
  
  CONCLUSIONS
  Cardiac myocyte KLF5 is a transcriptional regulator of Ppara and cardiac energetics.
authors.affiliation: From the Metabolic Biology Laboratory, Department of Pharmacology, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (K.D., C.J.P., M.-C.V.); Institute of Molecular Biosciences, University of Graz, Graz, Austria (N.M.P.); Howard Hughes Medical Institute, Department of Pathology, New York University School of Medicine (P.N., I.A.); Division of Endocrinology, Diabetes, and Metabolism, New York University-Langone School of Medicine (F.W., C.M.T., Y.H., I.J.G.); and Division of Molecular Cardiology, Department of Medicine, Texas A & M Health Science Center, Temple (S.G.). drosatos@temple.edu.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Drosatos
authors.affiliation: From the Metabolic Biology Laboratory, Department of Pharmacology, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (K.D., C.J.P., M.-C.V.); Institute of Molecular Biosciences, University of Graz, Graz, Austria (N.M.P.); Howard Hughes Medical Institute, Department of Pathology, New York University School of Medicine (P.N., I.A.); Division of Endocrinology, Diabetes, and Metabolism, New York University-Langone School of Medicine (F.W., C.M.T., Y.H., I.J.G.); and Division of Molecular Cardiology, Department of Medicine, Texas A & M Health Science Center, Temple (S.G.).
authors.forename: Nina M
authors.initials: NM
authors.lastname: Pollak
authors.affiliation: From the Metabolic Biology Laboratory, Department of Pharmacology, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (K.D., C.J.P., M.-C.V.); Institute of Molecular Biosciences, University of Graz, Graz, Austria (N.M.P.); Howard Hughes Medical Institute, Department of Pathology, New York University School of Medicine (P.N., I.A.); Division of Endocrinology, Diabetes, and Metabolism, New York University-Langone School of Medicine (F.W., C.M.T., Y.H., I.J.G.); and Division of Molecular Cardiology, Department of Medicine, Texas A & M Health Science Center, Temple (S.G.).
authors.forename: Christine J
authors.initials: CJ
authors.lastname: Pol
authors.affiliation: From the Metabolic Biology Laboratory, Department of Pharmacology, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (K.D., C.J.P., M.-C.V.); Institute of Molecular Biosciences, University of Graz, Graz, Austria (N.M.P.); Howard Hughes Medical Institute, Department of Pathology, New York University School of Medicine (P.N., I.A.); Division of Endocrinology, Diabetes, and Metabolism, New York University-Langone School of Medicine (F.W., C.M.T., Y.H., I.J.G.); and Division of Molecular Cardiology, Department of Medicine, Texas A & M Health Science Center, Temple (S.G.).
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Ntziachristos
authors.affiliation: From the Metabolic Biology Laboratory, Department of Pharmacology, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (K.D., C.J.P., M.-C.V.); Institute of Molecular Biosciences, University of Graz, Graz, Austria (N.M.P.); Howard Hughes Medical Institute, Department of Pathology, New York University School of Medicine (P.N., I.A.); Division of Endocrinology, Diabetes, and Metabolism, New York University-Langone School of Medicine (F.W., C.M.T., Y.H., I.J.G.); and Division of Molecular Cardiology, Department of Medicine, Texas A & M Health Science Center, Temple (S.G.).
authors.forename: Florian
authors.initials: F
authors.lastname: Willecke
authors.affiliation: From the Metabolic Biology Laboratory, Department of Pharmacology, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (K.D., C.J.P., M.-C.V.); Institute of Molecular Biosciences, University of Graz, Graz, Austria (N.M.P.); Howard Hughes Medical Institute, Department of Pathology, New York University School of Medicine (P.N., I.A.); Division of Endocrinology, Diabetes, and Metabolism, New York University-Langone School of Medicine (F.W., C.M.T., Y.H., I.J.G.); and Division of Molecular Cardiology, Department of Medicine, Texas A & M Health Science Center, Temple (S.G.).
authors.forename: Mesele-Christina
authors.initials: MC
authors.lastname: Valenti
authors.affiliation: From the Metabolic Biology Laboratory, Department of Pharmacology, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (K.D., C.J.P., M.-C.V.); Institute of Molecular Biosciences, University of Graz, Graz, Austria (N.M.P.); Howard Hughes Medical Institute, Department of Pathology, New York University School of Medicine (P.N., I.A.); Division of Endocrinology, Diabetes, and Metabolism, New York University-Langone School of Medicine (F.W., C.M.T., Y.H., I.J.G.); and Division of Molecular Cardiology, Department of Medicine, Texas A & M Health Science Center, Temple (S.G.).
authors.forename: Chad M
authors.initials: CM
authors.lastname: Trent
authors.affiliation: From the Metabolic Biology Laboratory, Department of Pharmacology, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (K.D., C.J.P., M.-C.V.); Institute of Molecular Biosciences, University of Graz, Graz, Austria (N.M.P.); Howard Hughes Medical Institute, Department of Pathology, New York University School of Medicine (P.N., I.A.); Division of Endocrinology, Diabetes, and Metabolism, New York University-Langone School of Medicine (F.W., C.M.T., Y.H., I.J.G.); and Division of Molecular Cardiology, Department of Medicine, Texas A & M Health Science Center, Temple (S.G.).
authors.forename: Yunying
authors.initials: Y
authors.lastname: Hu
authors.affiliation: From the Metabolic Biology Laboratory, Department of Pharmacology, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (K.D., C.J.P., M.-C.V.); Institute of Molecular Biosciences, University of Graz, Graz, Austria (N.M.P.); Howard Hughes Medical Institute, Department of Pathology, New York University School of Medicine (P.N., I.A.); Division of Endocrinology, Diabetes, and Metabolism, New York University-Langone School of Medicine (F.W., C.M.T., Y.H., I.J.G.); and Division of Molecular Cardiology, Department of Medicine, Texas A & M Health Science Center, Temple (S.G.).
authors.forename: Shaodong
authors.initials: S
authors.lastname: Guo
authors.affiliation: From the Metabolic Biology Laboratory, Department of Pharmacology, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (K.D., C.J.P., M.-C.V.); Institute of Molecular Biosciences, University of Graz, Graz, Austria (N.M.P.); Howard Hughes Medical Institute, Department of Pathology, New York University School of Medicine (P.N., I.A.); Division of Endocrinology, Diabetes, and Metabolism, New York University-Langone School of Medicine (F.W., C.M.T., Y.H., I.J.G.); and Division of Molecular Cardiology, Department of Medicine, Texas A & M Health Science Center, Temple (S.G.).
authors.forename: Iannis
authors.initials: I
authors.lastname: Aifantis
authors.affiliation: From the Metabolic Biology Laboratory, Department of Pharmacology, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (K.D., C.J.P., M.-C.V.); Institute of Molecular Biosciences, University of Graz, Graz, Austria (N.M.P.); Howard Hughes Medical Institute, Department of Pathology, New York University School of Medicine (P.N., I.A.); Division of Endocrinology, Diabetes, and Metabolism, New York University-Langone School of Medicine (F.W., C.M.T., Y.H., I.J.G.); and Division of Molecular Cardiology, Department of Medicine, Texas A & M Health Science Center, Temple (S.G.).
authors.forename: Ira J
authors.initials: IJ
authors.lastname: Goldberg
mesh_terms: D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D004734:Energy Metabolism; D005227:Fatty Acids / Q000378:metabolism; D005838:Genotype; D051741:Kruppel-Like Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D018805:Sepsis / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D015398:Signal Transduction; D051297:Sodium-Glucose Transporter 2 / Q000235:genetics / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013997:Time Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014280:Triglycerides / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D005227:Fatty Acids; C118391:Klf5 protein, mouse; D051741:Kruppel-Like Transcription Factors; D047493:PPAR alpha; D016755:Proto-Oncogene Proteins c-jun; C490299:Slc5a2 protein, mouse; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D014280:Triglycerides
keywords: PPAR alpha; cardiac myocyte; fatty acids; heart; heart failure