• Konstantinos Drosatos, Nina M Pollak, Christine J Pol, Panagiotis Ntziachristos, Florian Willecke, Mesele-Christina Valenti, Chad M Trent, Yunying Hu, Shaodong Guo, Iannis Aifantis, and Ira J Goldberg.
• 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.
• Circ. Res. 2016 Jan 22; 118 (2): 241-53.

RationaleFatty 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.ObjectiveTo determine the role of Krüppel-like factor 5 (KLF5) in transcriptional regulation of Ppara.Methods And ResultsWe 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.ConclusionsCardiac myocyte KLF5 is a transcriptional regulator of Ppara and cardiac energetics.© 2015 American Heart Association, Inc.

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