辅酶A类代谢中间产物参与组蛋白表观遗传修饰调控肝细胞代谢网络对高油脂营养应答的机制研究

Coenzyme A metabolic intermediates are a class of analogs with similar chemical structures that produced during cell metabolism. They function as the vehicles for material and energy transferring in cellular metabolism, as well as the modification group-donors in protein post-translational modification (PTM). It is well known that Coenzyme A metabolic intermediates’ material and energy transferring functions are guardian of metabolic balance. However, as bifunctional components, Coenzyme A metabolic intermediates’ function in protein PTM might also play significant roles in balancing cell metabolism, which are remaining elusive. Our previous studies have demonstrated that the lysine acetyltransferase 2A (KAT2A) can directly use different Coenzyme A metabolic intermediates to catalyze multiple types of histone modifications, which mainly distribute in gene promoter regions and correlate with the transcription level of genes, including genes in metabolism network. Aim to explore the roles of Coenzyme A metabolic intermediates and KAT2A-mediated histone modifications in regulating cell metabolism, we will use non-alcoholic fatty liver disease (NAFLD) model to study the effects of high-lipid nutrition on the nuclear distribution of Coenzyme A metabolic intermediates, the histone modification profiles that mediated by Coenzyme A metabolic intermediates and KAT2A, and the cellular metabolism profile that regulated by the KAT2A-mediated histone modifications. The efficacy of KAT2A inhibitor in NAFLD therapy will also be evaluated. With the accomplishments of the proposed studies, we will understand the mechanism underlying Coenzyme A metabolic intermediates-mediated histone modifications regulating the response of liver cell metabolism to high-lipid nutrition. The effect of KAT2A inhibitor on NAFLD will shed new light on the development of novel NAFLD clinical treatment strategies.

辅酶A类物质是糖脂代谢中担负物质能量转运的一类代谢中间产物，也是蛋白质翻译后修饰反应中重要的修饰基团供体。目前已有大量研究从物质能量传递介质的角度探索辅酶A类物质在细胞糖脂代谢失调中的作用，但鲜有研究从蛋白质翻译后修饰基团供体的角度探索辅酶A类物质对糖脂代谢失调的感应及对细胞代谢网络的调控。我们的前期工作发现赖氨酸乙酰转移酶KAT2A可用不同辅酶A类物质直接催化多种类型的组蛋白修饰，且这些修饰多发生在基因启动子区域并调控基因转录，包括代谢相关的基因转录。因此本申请课题从辅酶A类物质调控组蛋白修饰的机制出发，以非酒精性脂肪肝为模型，研究高油脂营养对肝细胞内辅酶A类物质在细胞核内分布的调控，阐明辅酶A类物质在KAT2A的催化下对肝细胞组蛋白表观遗传修饰图谱的调控及其对细胞代谢网络的改变，并验证其所调控的细胞代谢网络对高油脂的应答及对非酒精性脂肪肝形成的重要作用，探索非酒精性脂肪肝防治新策略。

酰基辅酶A类物质是细胞内糖脂代谢的重要中间产物，也是参与蛋白质翻译后修饰的重要修饰基团供体。本课题以KAT2A具有多种酰基转移酶活性的假设为切入点，发现KAT2A可直接用乙酰辅酶A、丙酰辅酶A、丁酰辅酶A、琥珀酰辅酶A催化核小体上共18个赖氨酸位点的多种酰基化修饰。通过结构生物学分析，本课题初步阐明了KAT2A对酰基辅酶A类底物的选择机制。肝细胞糖脂代谢网络的失调可能导致细胞内多种酰基辅酶A类物质分布的失调，这一失调信号通过KAT2A的多种酰基转移酶的活性转换成为相应的组蛋白酰基化修饰图谱，调控基因表达谱及细胞代谢网络的重塑。高油脂营养环境是诱导肝细胞内脂滴聚集和动物非酒精性脂肪肝的重要因素，抑制KAT2A可显著抑制高油脂诱导的细胞内脂滴聚集以及小鼠非酒精性脂肪肝，进一步提示KAT2A的多种酰基化修饰活性是肝细胞感受并应答高油脂营养环境的重要机制。本研究初步阐明了蛋白质酰基转移酶对酰基辅酶A类底物的选择机制，丰富了细胞代谢网络与组蛋白修饰图谱的互作机制，为高油脂诱导的非酒精性脂肪肝提供了新的潜在防治靶点。

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