The effect of ACC2 deletion on cardiac metabolism and function

描述（由申请人提供）：脂肪酸代谢对维持正常心脏的能量和功能至关重要。然而，代谢、能量学和功能障碍的改变已被记录在病理性肥大和心力衰竭中。这些代谢变化与以脂肪酸为代价增加对葡萄糖和乳酸盐的依赖一致，代表向胎儿代谢特征的逆转。随着心力衰竭的继续发展，由于脂肪酸产生的ATP减少而导致的能量剥夺成为衰竭心脏维持正常功能的能力的限制因素。虽然机制是难以捉摸的，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形成丙二酰辅酶A。随着丙二酰辅酶A水平的升高，脂肪酸通过肉毒碱棕榈酰转移酶I（CPTI）的转运受到抑制。因此，ACC 2可能是一个潜在的目标，其中修改脂肪氧化通过其对丙二酰辅酶A的作用。先前的研究证实，ACC 2全敲除小鼠表现出增加的脂肪酸氧化，同时减少丙二酰辅酶A在心脏组织中。因此，本研究的目的是通过在小鼠模型中靶向ACC 2来增强心脏脂肪酸氧化。本研究的具体假设是，伴随ACC 2缺失的脂肪酸氧化增加将维持肥大心脏中的线粒体功能和心肌能量学，从而防止向心力衰竭的转变。本研究的结果将解决心脏代谢领域的一个关键问题，并可能为心力衰竭患者的ACC2抑制剂药物干预提供见解。

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.