Authors

D. A. Prosdocimo; P. Anand; X. D. Liao; H. Zhu; S. Shelkay; P. Artero-Calderon; L. L. Zhang; J. Kirsh; D. Moore; M. G. Rosca; E. Vazquez; J. Kerner; K. M. Akat; Z. Williams; J. H. Zhao; H. Fujioka; T. Tuschl; X. D. Bai; P. C. Schulze; C. L. Hoppel; M. K. Jain;S. M. Haldar

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Abbreviated Journal Title

J. Biol. Chem.

Keywords

Cardiac Metabolism; Cardiovascular; Kruppel-like Factor (KLF); Lipid; Metabolism; Transcription Factors; FATTY-ACID OXIDATION; TRANSCRIPTIONAL COACTIVATOR PGC-1-ALPHA; HISTONE; ACETYLTRANSFERASE ACTIVITY; LARGE GENE LISTS; SKELETAL-MUSCLE; INSULIN-RESISTANCE; FAILING HEART; PPAR-ALPHA; TRANSPORT PROTEIN-1; ACTIVATION DOMAIN; Biochemistry & Molecular Biology

Abstract

Background: Metabolic homeostasis is central to normal cardiac function. The molecular mechanisms underlying metabolic plasticity in the heart remain poorly understood. Results: Kruppel-like factor 15 (KLF15) is a direct and independent regulator of myocardial lipid flux. Conclusion: KLF15 is a core component of the transcriptional circuitry that governs cardiac metabolism. Significance: This work is the first to implicate the KLF transcription factor family in cardiac metabolism. 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.

Journal Title

Journal of Biological Chemistry

Volume

289

Issue/Number

9

Publication Date

1-1-2014

Document Type

Article

Language

English

First Page

5914

Last Page

5924

WOS Identifier

WOS:000332015500048

ISSN

0021-9258

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