The effect of ACC2 deletion on cardiac metabolism and function

说明（申请人提供）：脂肪酸代谢是维持正常心脏能量和功能所必需的。然而，在病理性肥厚和心力衰竭中，代谢、能量学和功能障碍的改变已被证实。这些代谢变化与以脂肪酸为代价增加对葡萄糖和乳酸的依赖是一致的，代表了胎儿代谢谱的逆转。随着心力衰竭的进展，脂肪酸产生的ATP减少导致的能量剥夺，成为衰竭心脏维持正常功能能力的限制因素。虽然机制难以捉摸，但似乎调节脂肪酸代谢的关键代谢酶被下调。因此，可以想象，脂肪酸氧化的恢复可能对衰竭的心脏有益。乙酰辅酶a羧化酶2 （ACC2）的功能是催化乙酰辅酶a生成丙二酰辅酶a。当丙二酰辅酶a水平升高时，脂肪酸通过肉碱棕榈酰转移酶I （CPTI）的转运受到抑制。因此，ACC2可能是通过其对丙二酰辅酶a的作用来修饰脂肪氧化的潜在靶点。先前的研究证实，ACC2总敲除小鼠表现出脂肪酸氧化增加，同时心脏组织中丙二酰辅酶a减少。因此，本研究的目的是在小鼠模型中通过靶向ACC2来增强心脏脂肪酸氧化。本研究的具体假设是，随着ACC2缺失，脂肪酸氧化增加将维持肥大心脏的线粒体功能和心肌能量，从而防止过渡到心力衰竭。本研究的结果将解决心脏代谢领域的一个关键问题，并可能为ACC2抑制剂对心力衰竭患者的药物干预提供见解。

DESCRIPTION (provided by applicant): Fatty acid metabolism is essential to maintain energetics and function in the normal heart. However, alterations in metabolism, energetics, and dysfunction have been documented in pathological hypertrophy and heart failure. These metabolic changes are consistent with an increased reliance on glucose and lactate at the expense of fatty acids, representing a reversion to a fetal metabolic profile. As the progression of heart failure continues, energy deprivation, as a result of declining ATP production from fatty acids, becomes a limiting factor in the ability of the failing heart to sustain normal function. Although the mechanisms are elusive, it appears that key metabolic enzymes that regulate fatty acid metabolism are downregulated. Therefore, it is conceivable that restoration of fatty acid oxidation may be beneficial for the failing heart. The function acetyI CoA carboxylase 2 (ACC2) is to catalyze the formation of malonyl CoA from acetyl CoA. As malonyl CoA levels rise, fatty acid transport through carnitine palmitoyl transferase I (CPTI) is inhibited. Therefore, ACC2 may be a potential target in which to modify fatty oxidation through its action on malonyl CoA. Previous studies established that the ACC2 total knockout mouse demonstrated increased fatty acid oxidation with a concurrent reduction in malonyl CoA in cardiac tissue. Therefore, the purpose of the present study is to enhance cardiac fatty acid oxidation by targeting ACC2 in a mouse model. The specific hypothesis of this study is that the increased fatty acid oxidation accompanied by ACC2 deletion will sustain mitochondrial function and myocardial energetics in hypertrophied hearts, thus protecting from the transition to heart failure. The results of this study will address a critical question in the field of cardiac metabolism and may provide insight to the pharmacological intervention with ACC2 inhibitors for heart failure patients.