Extracellular Adenosine Inhibits Liver Gluconeogenesis via Adenosine Transporter ENT1 by Blocking of cAMP/p-PKA Signaling Pathway
Diabetes mellitus,which is characterized by disorders of glucose and lipid metabolism,has become a heavy global disease burden.Increasing evidences suggest that the adenosine system plays a key role in regulating insulin and glucose homeostasis.Adenosine is an important regulator of cellular metabolism and is in-volved in several physiopathological processes such as energy metabolism,immune regulation,and oxidative stress through activation of G protein-coupled receptors and nucleoside transporters.However,the role of adenosine in the regulation of hepatic gluconeogenesis has not been elucidated.This article verified the regulatory effect of adenos-ine on glucagon stimulated hepatic gluconeogenesis pathway after its transfer into the cytosol via ENT(equilibrative nucleoside transporter)at multiple levels.The results showed that exogenous adenosine inhibited blood glucose elevation in mice.In a cellular model,adenosine inhibited hepatic gluconeogenesis and thereby reduced glucose output in a dose-dependent manner with minimal cytotoxicity.The ENT was widely expressed in liver tissues and cells,and the ENT1 mediated the hepatic glucose output inhibited by adenosine.Furthermore,adenosine-mediated inhibition of gluconeogenesis was not dependent on activation of the AMPK pathway.After extracellular adenosine stimulation,the intracellular cAMP concentration was significantly reduced,the expression of phosphorylated PKA downstream proteins was significantly inhibited,and the cellular glycolytic output capacity was significantly re-duced,and this inhibition could be attenuated by ENT inhibitors but not by adenosine kinase inhibitors.The results showed that the transfer of extracellular adenosine into the cell via the nucleoside transporter ENT inhibited adenyl-ate cyclase activity,which in turn inhibited cAMP synthesis and the expression of phosphorylated PKA substrate proteins,inhibited hepatic gluconeogenesis,and ultimately reduced glucose output.
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