Konstantinos Drosatos1, Nina M Pollak2, Christine J Pol2, Panagiotis Ntziachristos2, Florian Willecke2, Mesele-Christina Valenti2, Chad M Trent2, Yunying Hu2, Shaodong Guo2, Iannis Aifantis2, Ira J Goldberg2. 1. 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. 2. 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.).
Abstract
RATIONALE: 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. METHODS AND 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.
RATIONALE: 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. METHODS AND 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.
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