Hepatic overexpression of ATP synthase β subunit activates PI3K/Akt pathway to ameliorate hyperglycemia of diabetic mice

ATP synthase β subunit (ATPSb) had been previously shown to play an important role in controlling ATP synthesis in pancreatic β-Cells. This study aimed to investigate the role of ATPSb in regulation of hepatic ATP content and glucose metabolism in diabetic mice. ATPSb expression and ATP content were both reduced in the livers of type 1 and type 2 diabetic mice. Hepatic overexpression of ATPSb elevated cellular ATP content and ameliorated hyperglycemia of streptozocininduced diabetic mice and db/db mice. ATPSb overexpression increased phosphorylated Akt (pAkt) levels and reduced PEPCK and G6pase expression levels in the livers. Consistently, ATPSb overexpression repressed hepatic glucose production in db/db mice. In cultured hepatocytes, ATPSb overexpression increased intracellular and extracellular ATP content, elevated the cytosolic free calcium level, and activated Akt independent of insulin. The ATPSb-induced increase in cytosolic free calcium and pAkt levels was attenuated by inhibition of P2 receptors. Notably, inhibition of calmodulin (CaM) completely abolished ATPSbinduced Akt activation in liver cells. Inhibition of P2 receptors or CaM blocked ATPSb-induced nuclear exclusion of forkhead box O1 in liver cells. In conclusion, a decrease in hepatic ATPSb expression in the liver, leading to the attenuation of ATP-P2 receptor-CaM-Akt pathway, may play an important role in the progression of diabetes.