Cardiac Myocyte KLF5 Regulates Ppara Expression and Cardiac Function

Konstantinos Drosatos*, Nina M. Pollak, Christine J. Pol, Panagiotis Ntziachristos, Florian Willecke, Mesele Christina Valenti, Chad M. Trent, Yunying Hu, Shaodong Guo, Iannis Aifantis, Ira J. Goldberg

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)241-253
Number of pages13
JournalCirculation research
Volume118
Issue number2
DOIs
StatePublished - Jan 22 2016

Keywords

  • PPAR alpha
  • cardiac myocyte
  • fatty acids
  • heart
  • heart failure

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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