State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Fujian, China.
Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Nat Metab. 2022 Oct;4(10):1369-1401. doi: 10.1038/s42255-022-00640-7. Epub 2022 Oct 10.
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.
5'-腺苷一磷酸激活蛋白激酶（AMPK）的活性与细胞内葡萄糖的可用性呈负相关。当葡萄糖水平较低时，糖酵解酶醛缩酶不会与果糖-1,6-二磷酸（FBP）结合，而是发出信号激活溶酶体 AMPK。在这里，我们表明，用小分子 aldometanib 阻断醛缩酶与 FBP 的结合，可选择性地激活溶酶体 AMPK，并在啮齿动物中产生有益的代谢效应。我们在醛缩酶抑制剂的筛选中发现 aldometanib，表明它可以防止 FBP 与 v-ATPase 相关的醛缩酶结合并激活溶酶体 AMPK，从而模拟细胞葡萄糖饥饿状态。在雄性小鼠中，aldometanib 可引起胰岛素非依赖性的血糖降低作用，而不会引起低血糖。Aldometanib 还可减轻肥胖雄性啮齿动物的脂肪肝和非酒精性脂肪性肝炎。此外，aldometanib 可延长秀丽隐杆线虫和小鼠的寿命和健康寿命。总之，aldometanib 模拟并采用与葡萄糖饥饿相关的溶酶体 AMPK 激活途径来发挥生理作用，并且可能有潜力成为人类代谢紊乱的治疗药物。
