The effect of ACC2 deletion on cardiac metabolism and function

描述(申请人提供)：脂肪酸代谢对于维持正常心脏的能量和功能是必不可少的。然而，在病理性肥厚和心力衰竭中，已经记录了代谢、能量和功能障碍的改变。这些代谢变化与对葡萄糖和乳酸的依赖增加，而对脂肪酸的依赖增加是一致的，代表着向胎儿代谢特征的回归。随着心力衰竭的继续发展，由于脂肪酸产生的ATP减少而导致的能量匮乏，成为衰竭心脏维持正常功能能力的限制因素。尽管机制尚不清楚，但似乎调节脂肪酸新陈代谢的关键代谢酶下调了。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。随着丙二酰辅酶A水平的升高，通过肉碱棕榈酰转移酶I(CPTI)的脂肪酸运输受到抑制。因此，ACC2可能是通过作用于丙二酰辅酶A来修饰脂肪氧化的潜在靶点。先前的研究证实，ACC2基因完全敲除的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，本研究的目的是通过在小鼠模型中靶向ACC2来增强心脏脂肪酸的氧化。这项研究的特定假设是，伴随ACC2缺失的脂肪酸氧化增加将维持肥厚心脏的线粒体功能和心肌能量，从而防止过渡到心力衰竭。这项研究的结果将解决心脏代谢领域的一个关键问题，并可能为心力衰竭患者使用ACC2抑制剂进行药物干预提供见解。

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.