TY - JOUR
T1 - Kruppel-like factor 15 is a critical regulator of cardiac lipid metabolism
AU - Prosdocimo, Domenick A.
AU - Anand, Priti
AU - Liao, Xudong
AU - Zhu, Han
AU - Shelkay, Shamanthika
AU - Artero-Calderon, Pedro
AU - Zhang, Lilei
AU - Kirsh, Jacob
AU - Moore, D'Vesharronne
AU - Rosca, Mariana G.
AU - Vazquez, Edwin
AU - Kerner, Janos
AU - Akat, Kemal M.
AU - Williams, Zev
AU - Zhao, Jihe
AU - Fujioka, Hisashi
AU - Tuschl, Thomas
AU - Bai, Xiaodong
AU - Schulze, P. Christian
AU - Hoppel, Charles L.
AU - Jain, Mukesh K.
AU - Haldar, Saptarsi M.
PY - 2014/2/28
Y1 - 2014/2/28
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M113.531384
DO - 10.1074/jbc.M113.531384
M3 - Article
C2 - 24407292
AN - SCOPUS:84896882746
SN - 0021-9258
VL - 289
SP - 5914
EP - 5924
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 9
ER -