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,Journal of Biological Chemistry

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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
Journal of Biological Chemistry ( IF 4.0 ) Pub Date : 2020-12-06 , DOI: 10.1074/jbc.ra120.016565
Lifeng Zheng ₁ , Chengbin Xie ₁ , Ju Zheng ₁ , Qiangrui Dong ₁ , Tengxiao Si ₁ , Jing Zhang ₁ , Sheng-Tao Hou ₂

Affiliation

促进中风后的大脑恢复具有挑战性，因为大脑中会产生过多的抑制分子，阻止其完全愈合。此外，所产生的抑制分子的全部范围尚不清楚。在这里，我们使用基于高灵敏度 UPLC-MS 的鸟枪脂质组学策略，半定量测量了从短暂性大脑中动脉闭塞 (MCAO) 恢复的小鼠大脑皮层中的脂质含量差异。使用涉及主成分分析（PCA）和正交偏最小二乘判别分析（OPLS-DA）的类比软独立建模（SIMCA）方法询问脂质组学数据。对 578 种已确认脂质的统计显示，84 种脂质在 MCAO/再灌注期间发生了差异变化。脂质的最动态变化发生在 MCAO 后 1 - 7 d 之间，而浓度在 MCAO 后 14 和 28 d 时已降至假手术组水平。定量分析揭示了再灌注1-7天期间PC(16:0/16:0)的减少和LPC(16:0)水平的增加(Spearman's Rs = -0.86)之间存在很强的单调关系。cPLA2 的抑制阻止了 PC(16:0/16:0) 和 LPC(16:0) 之间比例的变化，表明 PC 的 Land 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））通过引起细胞内钙内流而损害神经元生长锥的完整性和神经元活力。相反，PC(16:0/16:0) 显着抑制小胶质细胞分泌 IL-1β 和 TNF-α，限制神经炎症途径。一起，

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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

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 semi-quantitively 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 - 7 d post-MCAO, whereas concentrations had subsided to the Sham group level at 14 and 28 d post-MCAO. Quantitative analyses revealed a strong monotonic relationship between the reduction in PC(16:0/16:0) and the increase in LPC(16:0) levels (Spearman’s Rs = -0.86) during the 1-7 d 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.

更新日期：2020-12-07

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