An imbalanced ratio between PC(16:0/16:0) and LPC(16:0) revealed by lipidomics supports the role of the Lands cycle in ischemic brain injury.
An imbalanced ratio between PC(16:0/16:0) and LPC(16:0) revealed by lipidomics supports the role of the Lands cycle in ischemic brain injury.
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脂质组学揭示的 PC(16:0/16:0) 和 LPC(16:0) 之间的不平衡比例支持 Lands 循环在缺血性脑损伤中的作用。
DOI：
10.1074/jbc.ra120.016565
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Hou ST
中科院分区：
文献类型：
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作者：
Zheng L;Xie C;Zheng J;Dong Q;Si T;Zhang J;Hou ST
促进中风后的大脑恢复颇具挑战性，因为大脑中会产生大量抑制性分子，阻碍其完全愈合。此外，所产生的抑制性分子的全貌尚未得到充分了解。在此，我们采用基于超高效液相色谱 - 质谱（UPLC - MS）的高灵敏度鸟枪法脂质组学策略，对经历短暂大脑中动脉闭塞（MCAO）后处于恢复阶段的小鼠大脑皮层中的脂质含量差异进行了半定量测定。利用基于主成分分析（PCA）和正交偏最小二乘法判别分析（OPLS - DA）的软独立类比建模（SIMCA）方法对脂质组学数据进行了分析。对578种已确认脂质的统计结果显示，在MCAO /再灌注过程中有84种脂质发生了差异变化。脂质最剧烈的变化发生在MCAO后的1至7天，而在MCAO后14天和28天，其浓度已降至假手术组水平。定量分析表明，在再灌注的1至7天期间，磷脂酰胆碱（PC）（16:0/16:0）的减少与溶血磷脂酰胆碱（LPC）（16:0）水平的增加之间存在强烈的单调关系（斯皮尔曼相关系数Rs = - 0.86）。抑制胞质型磷脂酶A2（cPLA2）可阻止PC（16:0/16:0）与LPC（16:0）之间比例的变化，这表明PC的兰氏循环发生了改变。一系列体外研究表明，LPC（16:0）而非PC（16:0/16:0），通过引发细胞内钙内流，对神经元生长锥的完整性和神经元活力有害。相反，PC（16:0/16:0）显著抑制小胶质细胞分泌白细胞介素 - 1β（IL - 1β）和肿瘤坏死因子 - α（TNF - α），从而限制神经炎症通路。综上所述，这些数据支持了由兰氏循环维持的PC（16:0/16:0）与LPC（16:0）之间失衡的比例，在缺血恢复过程中对神经元损伤和小胶质细胞介导的炎症反应所起的作用。
Promoting brain recovery after stroke is challenging as a plethora of inhibitory molecules are produced in the brain preventing it from full healing. Moreover, the full scope of inhibitory molecules produced is not well understood. Here, using a high-sensitivity UPLC-MS-based shotgun lipidomics strategy, we semiquantitively measured the differential lipid contents in the mouse cerebral cortex recovering from a transient middle cerebral artery occlusion (MCAO). The lipidomic data were interrogated using the soft independent modeling of class analogy (SIMCA) method involving principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA). Statistics of the 578 confirmed lipids revealed 84 species were differentially changed during MCAO/reperfusion. The most dynamic changes in lipids occurred between 1 and 7 days post-MCAO, whereas concentrations had subsided to the Sham group level at 14 and 28 days post-MCAO. Quantitative analyses revealed a strong monotonic relationship between the reduction in phosphatidylcholine (PC)(16:0/16:0) and the increase in lysophosphatidylcholine (LPC)(16:0) levels (Spearman’s Rs = −0.86) during the 1 to 7 days reperfusion period. Inhibition of cPLA2 prevented changes in the ratio between PC(16:0/16:0) and LPC(16:0), indicating altered Land’s cycle of PC. A series of in vitro studies showed that LPC(16:0), but not PC(16:0/16:0), was detrimental to the integrity of neuronal growth cones and neuronal viability through evoking intracellular calcium influx. In contrast, PC(16:0/16:0) significantly suppressed microglial secretion of IL-1β and TNF-α, limiting neuroinflammation pathways. Together, these data support the role of the imbalanced ratio between PC(16:0/16:0) and LPC(16:0), maintained by Lands’ cycle, in neuronal damage and microglia-mediated inflammatory response during ischemic recovery.