HIF1α-神经酰胺鞘脂群代谢网络调控在高脂饮食加速动脉粥样硬化进程中的作用

The activation of endothelium is the primary event of atherosclerosis susceptibility. Dyslipidemia is the key point for the development of high-fat diet-induced atherosclerosis. Ceramide consists of a group of sphingolipids with metabolic activity. The role of of ceramide metabolism dynamic regulation in the development of high-fat diet-induced atherosclerosis remains unknown. We found that: The concentration of ceramide is increased in the development of high-fat diet-induced atherosclerosis. Ceramide induced the activation of endothelial inflammasome and increase endothelial inflammatory activation. HIF1α specific knock out in adipose tissue significantly inhibited the metabolism of ceramide. In this project, we will perform lipidomics to determine whether dynamic regulation of ceramide metabolism is involved in the development of high-fat diet-induced atherosclerosis, and investigate whether ceramide activate endothelial inflammasome and then aggravate atherosclerosis susceptibility. We will employ adipose tissue specific HIF1α knockout mice to determine the mechanisms how HIF1α regulates the metabolism of ceramide. Our aim is to investigate the key point of high-fat diet-accelerated atherosclerosis development. Our study will provide a new therapeutic target to prevent atherosclerosis initiation.

内皮细胞活化是动脉粥样硬化发生的初始事件，脂质代谢紊乱是高脂饮食加速动脉粥样硬化的关键节点。神经酰胺是一群具有代谢活性的鞘脂。神经酰胺鞘脂群代谢的调控在高脂加速动脉粥样硬化进程中的作用至今尚未阐明。我们预试验结果提示：在高脂加速动脉粥样硬化进程中，神经酰胺鞘脂群代谢显著增加；神经酰胺明显激活血管内皮细胞炎性小体以及增加血管内皮炎性活化；脂肪组织缺氧诱导因子-1a（HIF1a）可能参与神经酰胺鞘脂群代谢调控。本研究将基于脂质代谢组学技术，研究神经酰胺鞘脂群代谢的动态变化与高脂加速动脉粥样硬化进程之间的相关性；研究神经酰胺是否激活血管内皮细胞炎性小体以及是否通过炎性小体的激活参与动脉粥样硬化的发生；基于脂肪组织特异敲除小鼠模型，研究脂肪组织HIF1a是否调控神经酰胺鞘脂群代谢。此研究将探索逆转高脂加速动脉粥样硬化的关键靶点，为血管稳态与重构的调控机制提供新思路，对临床干预提供新策略。

神经酰胺鞘脂群代谢调控在高脂加速动脉粥样硬化发病中的作用至今尚未阐明。本项目研究发现脂肪细胞缺氧诱导因子HIF1促进神经酰胺合成，通过增加炎症与血浆胆固醇水平加剧动脉粥样硬化形成，提示脂肪细胞HIF1—神经酰胺代谢轴可以作为干预动脉粥样硬化的新靶点。并进一步扩展地研究了肠源神经酰胺代谢调控在代谢性疾病发病中的作用。相关的研究成果在Nature Medicine、Nature Review Endocrinology、Gastroenterology、Diabetes和EBioMedicine等杂志发表SCI 论文9篇（标注本项目基金号81470554）；获得1项国际专利（US 9,540,415 B2）。本项目负责人先后入选教育部“长江学者奖励计划”青年学者以及中组部“万人计划”青年拔尖人才。