Abstract：
Adaptation to hypoxia has attracted much public interest because of its clinical significance. However, hypoxic adaptation in the body is complicated and difficult to fully explore. To explore previously unknown conserved mechanisms and key proteins involved in hypoxic adaptation in different species, we first used a yeast model for mechanistic screening. Further multi-omics analyses in multiple species including yeast, zebrafish and mice revealed that glycerophospholipid metabolism was significantly involved in hypoxic adaptation with up-regulation of lysophospholipid acyltransferase (ALE1) in yeast, a key protein for the formation of dipalmitoyl phosphatidylcholine [DPPC (16:0/16:0)], which is a saturated phosphatidylcholine. Importantly, a mammalian homolog of ALE1, lysophosphatidylcholine acyltransferase 1 (LPCAT1), enhanced DPPC levels at the cell membrane and exhibited the same protective effect in mammalian cells under hypoxic conditions. DPPC supplementation effectively attenuated growth restriction, maintained cell membrane integrity and increased the expression of epidermal growth factor receptor under hypoxic conditions, but unsaturated phosphatidylcholine did not. In agreement with these findings, DPPC treatment could also repair hypoxic injury of intestinal mucosa in mice. Taken together, ALE1/LPCAT1-mediated DPPC formation, a key pathway of glycerophospholipid metabolism, is crucial for cell viability under hypoxic conditions. Moreover, we found that ALE1 was also involved in glycolysis to maintain sufficient survival conditions for yeast. The present study offers a novel approach to understanding lipid metabolism under hypoxia and provides new insights into treating hypoxia-related diseases.
摘要：
由于其临床意义，对缺氧的适应引起了公众的极大兴趣。然而,体内低氧适应是复杂的，难以充分探索。为了探索以前未知的保守机制和参与不同物种缺氧适应的关键蛋白，我们首先使用酵母模型进行机械筛选。在包括酵母在内的多个物种中进行进一步的多组学分析，斑马鱼和小鼠发现甘油磷脂代谢与酵母中溶血磷脂酰基转移酶（ALE1）的上调显著参与低氧适应，形成二棕榈酰磷脂酰胆碱[DPPC(16:0/16:0)]的关键蛋白，是一种饱和磷脂酰胆碱.重要的是,ALE1的哺乳动物同源物，溶血磷脂酰胆碱酰基转移酶1（LPCAT1），提高细胞膜上的DPPC水平，并在低氧条件下在哺乳动物细胞中表现出相同的保护作用。DPPC补充可有效减轻生长限制，在低氧条件下维持细胞膜完整性并增加表皮生长因子受体的表达，但不饱和磷脂酰胆碱没有。与这些发现一致，DPPC治疗还可以修复小鼠肠粘膜的缺氧损伤。一起来看,ALE1/LPCAT1介导的DPPC形成，甘油磷脂代谢的关键途径，对低氧条件下的细胞活力至关重要。此外，我们发现ALE1也参与糖酵解以维持酵母足够的存活条件。本研究提供了一种新的方法来理解缺氧下的脂质代谢，并为治疗缺氧相关疾病提供了新的见解。
