The aldolase inhibitor aldometanib mimics glucose starvation to activate lysosomal AMPK

ABSTRACT: 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 have screened for inhibitors that prevent FBP from binding to aldolase, and have identified Aldometanib that 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 (NASH) 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.

ORGANISM(S): Oryctolagus Cuniculus

SUBMITTER: Shengcai Lin  

PROVIDER: PXD035968 | iProX | Wed Aug 10 00:00:00 BST 2022

REPOSITORIES: iProX