Enhanced phosphocholine metabolism is essential for terminal erythropoiesis
Enhanced phosphocholine metabolism is essential for terminal erythropoiesis
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DOI：
10.1182/blood-2018-03-838516
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发表时间：
2018-06-28
期刊：
影响因子：
20.3
通讯作者：
Lodish, Harvey
中科院分区：
文献类型：
--
作者：
Huang, Nai-Jia;Lin, Ying-Cing;Lodish, Harvey
红细胞含有独特的膜脂质群。尽管人们对蛋白质表达的调节了解很多，但对红细胞生成过程中脂质代谢的调节研究却很少。在这里，我们表明，转录的磷酸1，磷酸乙醇胺和磷酸胆碱磷酸酶，介导的水解磷酸胆碱胆碱，强烈上调在人类和小鼠红细胞生成的红细胞生成的终末阶段，伴随着增加的磷脂酰胆碱（PC）和磷酸胆碱的catabolism所示的全球脂质组学分析小鼠和人类终末红细胞生成。PHOSPHO 1的消耗损害了胚胎小鼠和人类成红细胞的分化，并且在成年小鼠中，消耗损害了苯肼诱导的应激红细胞生成。PHOSPHO 1的丢失也损害了小鼠胎肝祖细胞中的磷酸胆碱催化剂，并导致几种脂质的积累;由于氧化磷酸化的减少，三磷酸腺苷（ATP）的产生减少。在PHOSPHO 1敲除的成红细胞中，糖酵解取代氧化磷酸化，增加的糖酵解用于丝氨酸或甘氨酸的产生。我们的研究阐明了终末红细胞生成过程中脂质代谢的动态变化，并揭示了PC和磷酸胆碱代谢在能量平衡和氨基酸供应中的关键作用。
Red cells contain a unique constellation of membrane lipids. Although much is known about regulated protein expression, the regulation of lipid metabolism during erythropoiesis is poorly studied. Here, we show that transcription of PHOSPHO1, a phosphoethanolamine and phosphocholine phosphatase that mediates the hydrolysis of phosphocholine to choline, is strongly upregulated during the terminal stages of erythropoiesis of both human and mouse erythropoiesis, concomitant with increased catabolism of phosphatidylcholine (PC) and phosphocholine as shown by global lipidomic analyses of mouse and human terminal erythropoiesis. Depletion of PHOSPHO1 impaired differentiation of fetal mouse and human erythroblasts, and, in adult mice, depletion impaired phenylhydrazine-induced stress erythropoiesis. Loss of PHOSPHO1 also impaired phosphocholine catabolism in mouse fetal liver progenitors and resulted in accumulation of several lipids; adenosine triphosphate (ATP) production was reduced as a result of decreased oxidative phosphorylation. Glycolysis replaced oxidative phosphorylation in PHOSPHO1-knockout erythroblasts and the increased glycolysis was used for the production of serine or glycine. Our study elucidates the dynamic changes in lipid metabolism during terminal erythropoiesis and reveals the key roles of PC and phosphocholine metabolism in energy balance and amino acid supply.