厦门大学林圣彩和张宸崧研究组合作发现低剂量二甲双胍通过 PEN2 靶向溶酶体AMP 活化蛋白激酶 (AMPK)通路。该项研究成果发表在2022年2月23日出版的《自然》上。
他们显示临床相关浓度的二甲双胍抑制溶酶体质子泵 v-ATP 酶，这是葡萄糖饥饿后 AMPK 激活的中心节点。他们合成了一种光活性二甲双胍探针，并将 PEN2（γ-分泌酶 7 的一个亚基）鉴定为二甲双胍的结合伴侣，其解离常数在微摩尔水平。二甲双胍结合的 PEN2 与 ATP6AP1（v-ATPase8 的一个亚基）形成复合物，导致 v-ATPase 的抑制和 AMPK 的激活，而不影响细胞 AMP 水平。敲除 PEN2 或重新引入不结合 ATP6AP1 的 PEN2 突变体会??减弱 AMPK 的激活。
在体内，Pen2 的肝脏特异性敲除消除了二甲双胍介导的肝脏脂肪含量的降低，而 Pen2 的肠道特异性敲除会削弱其降糖作用。此外，在秀丽隐杆线虫中敲除 pen-2 可消除二甲双胍诱导的寿命延长。总之，这些发现表明二甲双胍与 PEN2 结合并启动信号通路，该通路通过 ATP6AP1 与溶酶体葡萄糖传感通路相交，以激活 AMPK。这确保了二甲双胍在患者中发挥其治疗益处而没有明显的副作用。
据了解，二甲双胍是处方最多的抗糖尿病药物，已显示出其他益处，例如抗衰老和抗癌作用。对于二甲双胍的临床剂量，AMPK在其作用机制中起主要作用；然而，二甲双胍的直接分子靶点仍然未知。
附：英文原文
Title: Low-dose metformin targets the lysosomal AMPK pathway through PEN2
Author: Ma, Teng, Tian, Xiao, Zhang, Baoding, Li, Mengqi, Wang, Yu, Yang, Chunyan, Wu, Jianfeng, Wei, Xiaoyan, Qu, Qi, Yu, Yaxin, Long, Shating, Feng, Jin-Wei, Li, Chun, Zhang, Cixiong, Xie, Changchuan, Wu, Yaying, Xu, Zheni, Chen, Junjie, Yu, Yong, Huang, Xi, He, Ying, Yao, Luming, Zhang, Lei, Zhu, Mingxia, Wang, Wen, Wang, Zhi-Chao, Zhang, Mingliang, Bao, Yuqian, Jia, Weiping, Lin, Shu-Yong, Ye, Zhiyun, Piao, Hai-Long, Deng, Xianming, Zhang, Chen-Song, Lin, Sheng-Cai
Issue&Volume: 2022-02-23
Abstract: Metformin, the most prescribed antidiabetic medicine, has shown other benefits such as anti-ageing and anticancer effects1,2,3,4. For clinical doses of metformin, AMP-activated protein kinase (AMPK) has a major role in its mechanism of action4,5; however, the direct molecular target of metformin remains unknown. Here we show that clinically relevant concentrations of metformin inhibit the lysosomal proton pump v-ATPase, which is a central node for AMPK activation following glucose starvation6. We synthesize a photoactive metformin probe and identify PEN2, a subunit of γ-secretase7, as a binding partner of metformin with a dissociation constant at micromolar levels. Metformin-bound PEN2 forms a complex with ATP6AP1, a subunit of the v-ATPase8, which leads to the inhibition of v-ATPase and the activation of AMPK without effects on cellular AMP levels. Knockout of PEN2 or re-introduction of a PEN2 mutant that does not bind ATP6AP1 blunts AMPK activation. In vivo, liver-specific knockout of Pen2 abolishes metformin-mediated reduction of hepatic fat content, whereas intestine-specific knockout of Pen2 impairs its glucose-lowering effects. Furthermore, knockdown of pen-2 in Caenorhabditis elegans abrogates metformin-induced extension of lifespan. Together, these findings reveal that metformin binds PEN2 and initiates a signalling route that intersects, through ATP6AP1, the lysosomal glucose-sensing pathway for AMPK activation. This ensures that metformin exerts its therapeutic benefits in patients without substantial adverse effects.
DOI: 10.1038/s41586-022-04431-8
Source: https://www.nature.com/articles/s41586-022-04431-8
Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html
本期文章：《自然》：Online/在线发表
