title: Kruppel-like factor 15 is a critical regulator of cardiac lipid metabolism.
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.
authors.affiliation: From the Case Cardiovascular Research Institute and Harrington Heart and Vascular Institute.
authors.forename: Domenick A
authors.initials: DA
authors.lastname: Prosdocimo
authors.forename: Priti
authors.initials: P
authors.lastname: Anand
authors.forename: Xudong
authors.initials: X
authors.lastname: Liao
authors.forename: Han
authors.initials: H
authors.lastname: Zhu
authors.forename: Shamanthika
authors.initials: S
authors.lastname: Shelkay
authors.forename: Pedro
authors.initials: P
authors.lastname: Artero-Calderon
authors.forename: Lilei
authors.initials: L
authors.lastname: Zhang
authors.forename: Jacob
authors.initials: J
authors.lastname: Kirsh
authors.forename: D'Vesharronne
authors.initials: D
authors.lastname: Moore
authors.forename: Mariana G
authors.initials: MG
authors.lastname: Rosca
authors.forename: Edwin
authors.initials: E
authors.lastname: Vazquez
authors.forename: Janos
authors.initials: J
authors.lastname: Kerner
authors.forename: Kemal M
authors.initials: KM
authors.lastname: Akat
authors.forename: Zev
authors.initials: Z
authors.lastname: Williams
authors.forename: Jihe
authors.initials: J
authors.lastname: Zhao
authors.forename: Hisashi
authors.initials: H
authors.lastname: Fujioka
authors.forename: Thomas
authors.initials: T
authors.lastname: Tuschl
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Bai
authors.forename: P Christian
authors.initials: PC
authors.lastname: Schulze
authors.forename: Charles L
authors.initials: CL
authors.lastname: Hoppel
authors.forename: Mukesh K
authors.initials: MK
authors.lastname: Jain
authors.forename: Saptarsi M
authors.initials: SM
authors.lastname: Haldar
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000378:metabolism; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D050356:Lipid Metabolism; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C414172:KLF15 protein, human; C467418:Klf15 protein, mouse; C520013:Klf15 protein, rat; D051741:Kruppel-Like Transcription Factors; D009124:Muscle Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; C494361:Ep300 protein, mouse; C494362:Ep300 protein, rat
keywords: Cardiac Metabolism; Cardiovascular; Kruppel-like Factor (KLF); Lipid Metabolism; Transcription Factors