中国科学院上海有机化学研究所生物与化学交叉研究中心袁钧瑛等研究人员合作发现，精胺通过介导RIPK1的乙酰假丝酰化来抑制糖尿病的发生和进展。2024年11月7日，《自然—细胞生物学》杂志在线发表了这项成果。

研究人员表示，N-乙酰转移酶（小鼠NAT1（mNAT1）和人类NAT2（hNAT2））在2型糖尿病中介导胰岛素敏感性。研究人员发现mNAT1缺失导致细胞中精胺（一种具有健康保护和抗衰老作用的天然多胺）水平下降，但其机制尚不完全明了。

研究人员鉴定出mNAT1和hNAT2调节一种后转译修饰类型，即精胺乙酰化修饰，被命名为乙酰假丝酰化。这种修饰发生在受体相互作用丝氨酸/苏氨酸蛋白激酶1（RIPK1）上，RIPK1是炎症和细胞死亡的关键调节因子。精胺补充能够减少RIPK1介导的细胞死亡以及NAT1缺失引发的糖尿病表型。此外，通过抑制RIPK1，可以阻止由血管病理引起的NAT1缺失小鼠的胰岛素抗性和糖尿病肾病。

最后，研究人员还发现，在糖尿病患者的血管组织中，精胺水平下降且RIPK1被激活。该研究提示血管病理在糖尿病的发生和进展中发挥作用，并确定抑制RIPK1激酶可能成为治疗2型糖尿病的潜在治疗方法。

附：英文原文

Title: Spermidine mediates acetylhypusination of RIPK1 to suppress diabetes onset and progression

Author: Zhang, Tian, Fu, Weixin, Zhang, Haosong, Li, Jianlong, Xing, Beizi, Cai, Yuping, Zhang, Mengmeng, Liu, Xuheng, Qi, Chunting, Qian, Lihui, Hu, Xinbo, Zhu, Hua, Yang, Shuailong, Zhang, Min, Liu, Jianping, Li, Ganquan, Li, Yang, Xiang, Rong, Qi, Zhengqiang, Hu, Junhao, Li, Ying, Zou, Chengyu, Wang, Qin, Jin, Xia, Pang, Rui, Li, Peiying, Liu, Junli, Zhang, Yaoyang, Wang, Zhaoyin, Zhu, Zheng-Jiang, Shan, Bing, Yuan, Junying

Issue&Volume: 2024-11-07

Abstract: It has been established that N-acetyltransferase (murine NAT1 (mNAT1) and human NAT2 (hNAT2)) mediates insulin sensitivity in type 2 diabetes. Here we show that mNAT1 deficiency leads to a decrease in cellular spermidine—a natural polyamine exhibiting health-protective and anti-ageing effects—but understanding of its mechanism is limited. We identify that mNAT1 and hNAT2 modulate a type of post-translational modification involving acetylated spermidine, which we name acetylhypusination, on receptor-interacting serine/threonine-protein kinase 1 (RIPK1)—a key regulator of inflammation and cell death. Spermidine supplementation decreases RIPK1-mediated cell death and diabetic phenotypes induced by NAT1 deficiency in vivo. Furthermore, insulin resistance and diabetic kidney disease mediated by vascular pathology in NAT1-deficient mice can be blocked by inhibiting RIPK1. Finally, we demonstrate a decrease in spermidine and activation of RIPK1 in the vascular tissues of human patients with diabetes. Our study suggests a role for vascular pathology in diabetes onset and progression and identifies the inhibition of RIPK1 kinase as a potential therapeutic approach for the treatment of type 2 diabetes.

DOI: 10.1038/s41556-024-01540-6

Source: https://www.nature.com/articles/s41556-024-01540-6