The aldolase inhibitor aldometanib mimics glucose starvation to activate lysosomal AMPK.
The aldolase inhibitor aldometanib mimics glucose starvation to activate lysosomal AMPK.
复制标题
醛缩酶抑制剂阿美他尼模拟葡萄糖饥饿来激活溶酶体 AMPK
DOI：
10.1038/s42255-022-00640-7
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发表时间：
2022-10
影响因子：
20.8
通讯作者：
Lin, Sheng-Cai
中科院分区：
文献类型：
--
作者：
Zhang, Chen-Song;Li, Mengqi;Wang, Yu;Li, Xiaoyang;Zong, Yue;Long, Shating;Zhang, Mingliang;Feng, Jin-Wei;Wei, Xiaoyan;Liu, Yan-Hui;Zhang, Baoding;Wu, Jianfeng;Zhang, Cixiong;Lian, Wenhua;Ma, Teng;Tian, Xiao;Qu, Qi;Yu, Yaxin;Xiong, Jinye;Liu, Dong-Tai;Wu, Zhenhua;Zhu, Mingxia;Xie, Changchuan;Wu, Yaying;Xu, Zheni;Yang, Chunyan;Chen, Junjie;Huang, Guohong;He, Qingxia;Huang, Xi;Zhang, Lei;Sun, Xiufeng;Liu, Qingfeng;Ghafoor, Abdul;Gui, Fu;Zheng, Kaili;Wang, Wen;Wang, Zhi-Chao;Yu, Yong;Zhao, Qingliang;Lin, Shu-Yong;Wang, Zhi-Xin;Piao, Hai-Long;Deng, Xianming;Lin, Sheng-Cai
The activity of 5′-adenosine monophosphate-activated protein kinase (AMPK) is inversely correlated with the cellular availability of glucose. When glucose levels are low, the glycolytic enzyme aldolase is not bound to fructose-1,6-bisphosphate (FBP) and, instead, signals to activate lysosomal AMPK. Here, we show that blocking FBP binding to aldolase with the small molecule aldometanib selectively activates the lysosomal pool of AMPK and has beneficial metabolic effects in rodents. We identify aldometanib in a screen for aldolase inhibitors and show that it prevents FBP from binding to v-ATPase-associated aldolase and activates lysosomal AMPK, thereby mimicking a cellular state of glucose starvation. In male mice, aldometanib elicits an insulin-independent glucose-lowering effect, without causing hypoglycaemia. Aldometanib also alleviates fatty liver and nonalcoholic steatohepatitis in obese male rodents. Moreover, aldometanib extends lifespan and healthspan in both Caenorhabditis elegans and mice. Taken together, aldometanib mimics and adopts the lysosomal AMPK activation pathway associated with glucose starvation to exert physiological roles, and might have potential as a therapeutic for metabolic disorders in humans. A small-molecule aldolase inhibitor, aldolazin is reported and shown to selectively activate the lysosomal pool of AMPK, which has glucose-lowering effects in rodents.
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DOI：
10.1126/science.1196371
发表时间：
2011-01-28
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
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Shaw RJ
DOI：
10.1073/pnas.2025932118
发表时间：
2021-09-14
影响因子：
11.1
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Yan Z
DOI：
10.1111/j.1432-1033.1990.tb15293.x
发表时间：
1990-01-12
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
DAVIES, SP;SIM, ATR;HARDIE, DG
通讯作者：
HARDIE, DG
影响因子：
4.6
作者：
Du Preez, G.;Fourie, H.;Wepener, V
通讯作者：
Wepener, V
影响因子：
2.9
作者：
Choi, KH;Shi, J;Allen, KN
通讯作者：
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