Kruppel-like factor 15 is a critical regulator of cardiac lipid metabolism

Domenick A. Prosdocimo, Priti Anand, Xudong Liao, Han Zhu, Shamanthika Shelkay, Pedro Artero-Calderon, Lilei Zhang, Jacob Kirsh, D'Vesharronne Moore, Mariana G. Rosca, Edwin Vazquez, Janos Kerner, Kemal M. Akat, Zev Williams, Jihe Zhao, Hisashi Fujioka, Thomas Tuschl, Xiaodong Bai, P. Christian Schulze, Charles L. HoppelMukesh K. Jain, Saptarsi M. Haldar

Research output: Contribution to journalArticle

60 Scopus citations

Abstract

The mammalian heart, the body's largest energy consumer, has evolved robust mechanisms to tightly couple fuel supply with energy demand across a wide range of physiologic and pathophysiologic states, yet, when compared with other organs, relatively little is known about the molecular machinery that directly governs metabolic plasticity in the heart. Although previous studies have defined Kruppel-like factor 15 (KLF15) as a transcriptional repressor of pathologic cardiac hypertrophy, a direct role for the KLF family in cardiac metabolism has not been previously established. We show in human heart samples that KLF15 is induced after birth and reduced in heart failure, a myocardial expression pattern that parallels reliance on lipid oxidation. Isolated working heart studies and unbiased transcriptomic profiling in Klf15-deficient hearts demonstrate that KLF15 is an essential regulator of lipid flux and metabolic homeostasis in the adult myocardium. An important mechanism by which KLF15 regulates its direct transcriptional targets is via interaction with p300 and recruitment of this critical co-activator to promoters. This study establishes KLF15 as a key regulator of myocardial lipid utilization and is the first to implicate the KLF transcription factor family in cardiac metabolism.

Original languageEnglish (US)
Pages (from-to)5914-5924
Number of pages11
JournalJournal of Biological Chemistry
Volume289
Issue number9
DOIs
StatePublished - Feb 28 2014

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Prosdocimo, D. A., Anand, P., Liao, X., Zhu, H., Shelkay, S., Artero-Calderon, P., Zhang, L., Kirsh, J., Moore, DV., Rosca, M. G., Vazquez, E., Kerner, J., Akat, K. M., Williams, Z., Zhao, J., Fujioka, H., Tuschl, T., Bai, X., Schulze, P. C., ... Haldar, S. M. (2014). Kruppel-like factor 15 is a critical regulator of cardiac lipid metabolism. Journal of Biological Chemistry, 289(9), 5914-5924. https://doi.org/10.1074/jbc.M113.531384