KLF15 in Cardiac Metabolism

描述(申请人提供)：心脏是一种耐力机器，需要持续高水平的能量供应才能在一生中保持其机械功能。因此，心脏有能力利用多种燃料来源来满足这一能量需求。虽然成人心脏优先消耗脂肪酸(FA)而不是碳水化合物(如葡萄糖)，但心肌的燃料可塑性对生物体的生存至关重要。例如，在某些生理(如运动和禁食)和病理(糖尿病)情况下，心脏会增加对脂肪酸的依赖。然而，在其他病理情况下(缺血、心力衰竭)， 碳水化合物(如葡萄糖)与脂肪的相对使用量增加。这种依赖于环境的底物选择至少部分地在基因调控水平上受到控制。鉴于心脏病在世界范围内的流行，彻底了解控制心脏燃料利用的基本基因调控机制至关重要。具有讽刺意味的是，尽管FA是人体最耗能的器官，而且FA优先于葡萄糖的利用，但体内心脏脂肪代谢的内源性转录调节因子的研究相对较少。我们实验室发表的研究表明，KLF15对于心脏适应机械和药物应激的能力是必不可少的。形成这一应用基础的初步观察现在确定KLF15是一种新的心脏脂质代谢调节因子。具体地说，心脏KLF15被发现受到各种生理和病理刺激的调节，这些刺激改变了燃料的利用。来自KLF15-/-小鼠的心脏显示出粮农组织降低的比率和对控制心肌FA利用、运输和氧化的目标的协调效应。在机制上，KLF15被发现与PPAR？合作，诱导对心肌脂类利用至关重要的靶基因子集。这些观察结果为这一应用的中心假设提供了基础，即KLF15-PPAR？分子模块调节心脏脂质代谢。为了更好地了解KLF15在心脏脂质代谢中的作用，我们提出了三个强大且相互关联的目标。在目标1中，我们将阐明控制心脏KLF15表达的上游生理信号。在目标2中，我们将确定KLF15-PPARa轴在心脏粮农组织中的分子基础和生理意义。最后，在目标3中，我们将确定KLF15-PPARa轴在心脏代谢应激状态中的作用。总而言之，这些研究应该阐明KLF15在心脏代谢中的作用，并可能为治疗心脏病的新方法提供基础。

DESCRIPTION (provided by applicant): 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.