The heart is an endurance machine that requires a continually high level of energy supply to maintain its mechanical function throughout life. As such, the heart has the capacity to utilize multiple fuel sources to meet this energy requirement. While the adult heart preferentially consumes fatty acids (FA) over carbohydrates (e.g. glucose), myocardial fuel plasticity is essential for organismal survival. For example, during certain physiologic (e.g. exercise and fasting) and pathologic (diabetes) conditions, the heart augments its reliance on fatty acids. However, in other pathologic conditions (ischemia, heart failure), the relative use of carbohydrates (e.g. glucose) to lipids is increased. This context dependent substrate selection is governed, at least in part, at the gene regulatory level. Given the worldwide epidemic of heart disease, a thorough understanding of the basic gene-regulatory mechanisms governing cardiac fuel utilization is of critical importance. Ironically, despite being the highest energy-consuming organ of the body, and given the preferential utilization of FA over glucose, studies of endogenous transcriptional regulators of cardiac lipid metabolism in vivo are relatively scarce. Published work from our laboratory demonstrates that KLF15 is essential for the heart's ability to adapt to mechanical and pharmacologic stress. Nascent observations that form the basis of this application now identify KLF15 as a novel regulator of cardiac lipid metabolism. Specifically, cardiac KLF15 was found to be regulated by diverse physiologic and pathologic stimuli that alter fuel utilization. Hearts from Klf15-/- mice demonstrate reduced FAO rates and concordant effects on targets controlling myocardial FA utilization, transport, and ?-oxidation. Mechanistically, KLF15 was found to cooperate with PPAR? to induce a subset of target genes critical for myocardial lipid utilization. These observations provide the foundation for the central hypothesis of this application that a KLF15- PPAR? molecular module regulates cardiac lipid metabolism. To better understand the role of KLF15 in cardiac lipid metabolism, three robust and interrelated aims are proposed.
In aim 1, we will elucidate the upstream physiologic signals governing cardiac KLF15 expression.
In aim 2, we will determine the molecular basis and physiologic importance of the KLF15-PPARa axis in cardiac FAO. And finally, in aim 3, we will determine the role of the KLF15-PPARa axis in states of cardiometabolic stress. Collectively, these studies should clarify the role of KLF15 in cardiac metabolism and potentially provide a foundation for novel approaches to the treatment of heart disease.

Public Health Relevance

The heart requires a continually high level of energy to maintain its mechanical function and perturbation of myocardial fuel utilization can contribute to a broad spectrum of disease state such as diabetic cardiomyopathy and heart failure. In this application, we reveal a novel molecular module that governs cardiac fuel utilization. The fact that this pathway is altered in physiologic and pathologic states suggests that a better understanding may provide the foundation for novel therapies aimed at the treatment of heart disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Special Emphasis Panel (ZRG1-CVRS-M (02))
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Wang, Lan-Hsiang
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Case Western Reserve University
Internal Medicine/Medicine
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United States
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Takeuchi, Yoshinori; Yahagi, Naoya; Aita, Yuichi et al. (2016) KLF15 Enables Rapid Switching between Lipogenesis and Gluconeogenesis during Fasting. Cell Rep 16:2373-86
Sun, Haipeng; Olson, Kristine C; Gao, Chen et al. (2016) Catabolic Defect of Branched-Chain Amino Acids Promotes Heart Failure. Circulation 133:2038-49
Morrison-Nozik, Alexander; Anand, Priti; Zhu, Han et al. (2015) Glucocorticoids enhance muscle endurance and ameliorate Duchenne muscular dystrophy through a defined metabolic program. Proc Natl Acad Sci U S A 112:E6780-9
Han, Shuxin; Han, Sean Shuxin; Zhang, Rongli et al. (2015) Circadian control of bile acid synthesis by a KLF15-Fgf15 axis. Nat Commun 6:7231
Prosdocimo, Domenick A; John, Jenine E; Zhang, Lilei et al. (2015) KLF15 and PPARα Cooperate to Regulate Cardiomyocyte Lipid Gene Expression and Oxidation. PPAR Res 2015:201625
Prosdocimo, Domenick A; Sabeh, M Khaled; Jain, Mukesh K (2015) Kruppel-like factors in muscle health and disease. Trends Cardiovasc Med 25:278-87
Liao, Xudong; Zhang, Rongli; Lu, Yuan et al. (2015) Kruppel-like factor 4 is critical for transcriptional control of cardiac mitochondrial homeostasis. J Clin Invest 125:3461-76
Zhang, Lilei; Prosdocimo, Domenick A; Bai, Xiaodong et al. (2015) KLF15 Establishes the Landscape of Diurnal Expression in the Heart. Cell Rep 13:2368-75
Tandler, Bernard; Fujioka, Hisashi; Hoppel, Charles L et al. (2015) Megamitochondria in Cardiomyocytes of a Knockout (Klf15-/-) Mouse. Ultrastruct Pathol 39:336-9
Tugal, Derin; Jain, Mukesh K; Simon, Daniel I (2014) Endothelial KLF4: crippling vascular injury? J Am Heart Assoc 3:e000769

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