心肌肥大是心脏对环境应激所致能量匮乏的适应过程。为适应能量需求，肥大心肌细胞发生代谢重编程，但其能量代谢方式及机制尚不清楚。我们前期工作发现，尿素通道蛋白B（UT-B）缺失小鼠随鼠龄进展为心肌肥大并伴脂质堆积、糖酵解增加、三羧酸循环（TCA）速度下降和ATP-柠檬酸裂解酶（Acly）表达增加。由此推测UT-B缺失小鼠心肌主要依赖糖酵解供能，糖酵解生成丙酮酸穿梭入线粒体进入TCA用于合成柠檬酸，后者再通过柠檬酸转运系统进入细胞质，在Acly的作用下裂解成乙酰辅酶A用于脂质从头合成，引发脂质代谢重构。本项目拟利用UT-B缺失小鼠模型以及高尿素和UT-B缺失细胞模型，观察调控Acly表达或翻译后修饰前后糖代谢产物及脂肪生成的变化，明确Acly参与高尿素所致心肌细胞脂质代谢重构，并阐明其分子机制，为心肌肥大干预提供新的策略和潜在的药物治疗靶点。

Myocardial hypertrophy is an important adaptation to energy deficiency caused by environmental stress. To meet the energy demand, hypertrophic myocardial cells use metabolic re-programming mode. However, the energy metabolism pattern and the corresponding mechanisms are not clear. Our previous study showed that urea transporter B（UT-B） null mice would suffer from hypertrophy following by increase of lipid accumulation, glycolysis and ATP citrate lyase（Acly） expression, decrease of TCA efficiency would be exaggerated with aging. These data indicate that the myocardial cells energy supporting is provided by the glycolytic pathway, and pyruvate from glycolysis is transferred into mitochondria for citrate synthesis. Then, the citrate is transpored into the cytoplasm by citrate transport system, which can be transformed to acetyl-coenzyme A (AcCoA) with the help of Acly. Then AcCoA is available to de novo synthesis of lipids, resulting in lipid synthesis, and lipid metabolic remodeling, this may be the mechanism of myocardial hypertrophy in UT-B null mice. Based on the previous study, we will establish UT-B null mice model and high urea or UT-B-deficient cell model, regulate the expression or post-translational modification of Acly, comprehensively observes glucose metabolic product and lipogenesis, illuminate the role of Acly in lipid metabolic remodeling of myocardial cells by high urea loaded, and clarify the the corresponding molecular mechanisms. To provide a new strategy and potential drug targets for hypertrophy invention and treatment.