非靶向脂质组学揭示巨噬细胞泡沫化进程脂质代谢功能失调

Untargeted Lipidomics Reveals Lipid Metabolism Dysfunction During Macrophage Foaming

动脉粥样硬化是一种多因素驱动的慢性复杂性疾病,主要特征为动脉内壁的脂质积累、炎症反应以及最终的纤维斑块形成.斑块的形成始于异常累积的脂质被动脉壁内的巨噬细胞吞噬,形成所谓的泡沫细胞.尽管泡沫细胞的形成在血管病理性重塑进程中扮演着核心角色,但目前对巨噬细胞泡沫化进程中脂质代谢紊乱的深入研究还相对欠缺.本文构建并优化了脂质组学分析流程,并将该流程用于巨噬细胞泡沫化进程中的代谢重编程分析,共鉴定到16个脂质亚类的645个脂质分子.使用主成分分析、时间序列模式分析和火山图分析,揭示了不同时期的泡沫细胞脂质水平存在显著差异.随着氧化低密度脂蛋白孵育时间延长,泡沫细胞脂质代谢失调程度增加,脂质亚类中甘油三酯、溶血磷脂、醚磷脂水平上调,而磷脂酰丝氨酸水平下调.甘油三酯的显著累积增强了巨噬细胞的炎症反应,通过进一步吞噬氧化低密度脂蛋白促进了泡沫细胞的形成;同时,磷脂酰丝氨酸和溶血磷脂酰胆碱在泡沫细胞晚期合成显著增加,表明泡沫化进程与细胞凋亡正相关,这些脂质分子可能作为信号分子趋化巨噬细胞对凋亡细胞的清除.本文不仅揭示了巨噬细胞在泡沫化进程中炎症反应的显著上调,还阐明了脂质代谢紊乱与细胞凋亡信号传递之间的紧密联系.

Atherosclerosis is a multifactorial chronic complex disease characterized by the accumulation of lipids,inflammatory responses,and ultimately fibrous plaque formation within arterial walls.Plaque formation begins with the abnormal accumulation of lipids engulfed by macrophages within arterial walls,forming so-called foam cells.Despite the pivotal role of foam cell formation in the pathophysiological remodeling process of blood vessels,in-depth research into lipid metabolism disturbances during macrophage foam cell formation is still relatively lacking.In this study,we constructed and optimized a lipidomics analysis workflow,applying it to analyzing metabolic reprogramming during macrophage foam cell formation.A total of 645 lipid molecules belonging to 16 lipid subclasses were identified.Principal component analysis,time-series pattern analysis,and volcano plot analysis revealed significant differences in lipid levels at different stages of foam cell formation.As incubation time with oxidized low-density lipoprotein increased,the degree of lipid metabolism dysfunction in foam cells increased.Triglycerides,hemolytic phospholipids,and ether phospholipids were upregulated,while phosphatidylserine was downregulated.The significant accumulation of triglycerides enhanced the inflammatory response of macrophages,promoting foam cell formation by further engulfing oxidized low-density lipoprotein.Meanwhile,the synthesis of phosphatidylserine and hemolytic phosphatidylcholine increased significantly in the late stages of foam cell formation,indicating a positive correlation between foam cell formation and cell apoptosis.These lipid molecules may serve as signaling molecules to attract macrophages for the clearance of apoptotic cells.This study not only reveals the significant upregulation of inflammatory responses during foam cell formation but also elucidates the close connection between lipid metabolism disturbances and cell apoptosis signaling.