调节器
转录因子
心力衰竭
生物
脂质代谢
转录组
激活剂(遗传学)
细胞生物学
转录调控
内科学
内分泌学
生物化学
医学
基因表达
基因
作者
Domenick A. Prosdocimo,Priti Anand,Xudong Liao,Han Zhu,Shamanthika Shelkay,Pedro Artero-Calderon,Lilei Zhang,Jacob Kirsh,D'Vesharronne V. Moore,Mariana G. Roșca,Edwin J. Vazquez,János Kerner,Kemal M. Akat,Zev Williams,Jihe Zhao,Hisashi Fujioka,Thomas Tuschl,Xiaodong Bai,P. Christian Schulze,Charles L. Hoppel,Mukesh K. Jain,Saptarsi M. Haldar
标识
DOI:10.1074/jbc.m113.531384
摘要
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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