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斯芬哥辛-1-酸盐通过PP2A抑制GLUT活性,并抵消糖尿病红细胞中的高血糖症

Nadine Thomas¹, Nathalie H Schröder¹, Melissa K Nowak¹

¹Institute of Molecular Medicine III, Heinrich Heine University, Düsseldorf, Germany.

Nature communications

|December 14, 2023

概括

红细胞通过控制葡萄糖运输体,通过黄素-1-酸盐 (S1P) 调节葡萄糖的吸收. 这种机制保护糖尿病患者的红细胞,并提供治疗点.

科学领域:

生物化学生化学
细胞生物学细胞生物学
代谢研究研究代谢研究

背景情况:

红细胞 (RBC) 是循环中的斯芬戈-1-酸盐 (S1P) 的主要载体.
斯芬哥辛-1-酸盐 (S1P) 在细胞代谢和信号通路中起着至关重要的作用.

研究的目的:

研究红细胞S1P含量在调节葡萄糖摄取和代谢流量的作用.
阐明S1P影响红细胞中葡萄糖运输的机制.
探索针对这种S1P介导途径用于糖尿病治疗干预的潜力.

主要方法:

在红细胞中S1P合成和运输的遗传和药理学操纵.
分析葡萄糖吸收,代谢流量和葡萄糖载体 (GLUT) 定位.
研究蛋白酸酶2A (PP2A) 活性和GLUT酸化.
在高血糖条件下对氧化应激的红细胞保护的评估.
使用淘汰赛小鼠模型 (Mfsd2b-/-) 来验证体内相关性.

主要成果:

红细胞S1P含量的变化直接调节葡萄糖吸收和代谢流量.
S1P激活PP2A,导致细胞表面GLUTs减少和葡萄糖吸收减少.
这种机制在糖尿病条件下得到增强,增加S1P合成和PP2A活性.
红细胞通过S1P介导的酸路径的激活来保护红细胞免受高血糖引起的脂质过氧化.
缺乏S1P出口者MFSD2B的小鼠对糖尿病引起的HbA1c升高和氧化损伤具有抗性.

结论:

红细胞S1P含量是葡萄糖代谢的关键调节者,通过S1P-PP2A-GLUT轴影响葡萄糖吸收.
这条通路在高血糖和糖尿病条件下为红细胞提供保护机制.
对fingolimod等药理学药物有反应的S1P途径,代表了糖尿病和相关并发症的有希望的治疗标.

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