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。

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.