Hepatic overexpression of ATP synthase β subunit activates PI3K/Akt pathway to ameliorate hyperglycemia of diabetic mice
- Chunjiong Wang1,2,#,
- Zhenzhen Chen1,#,
- Sha Li1,#,
- Yuan Zhang3,
- Shi Jia1,
- Jing Li1,
- Yujing Chi1,
- Yifei Miao1,
- Youfei Guan1,4 and
- Jichun Yang1,*
- 1 Department of Physiology and Pathophysiology, Key Laboratory of Molecular Cardiovascular Science Peking (Beijing) University Health Science Center Beijing 100191, China
- 2 Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin 300070, China
- 3 Department of Laboratory Medicine, Peking University Third Hospital, Beijing 100191, China
- 4 Shenzhen University Diabetes Center, Shenzhen University Health Science Center, Shenzhen 518060, China
- *Corresponding author: Jichun Yang, E-mail:
# These authors contributed equally to this work
ATP synthase β subunit (ATPSβ) 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 ATPSβ in regulation of hepatic ATP content and glucose metabolism in diabetic mice. Both ATPSβ expression and ATP content were reduced in the livers of type 1 and type 2 diabetic mice. Hepatic overexpression of ATPSβ elevated cellular ATP content, and ameliorated hyperglycemia of STZ-induced diabetic mice and db/db mice. ATPSβ overexpression increased phosphorylated Akt (pAkt) levels and reduced PEPCK and G6pase expression levels in the livers. Consistently, ATPSβ overexpression repressed hepatic glucose production in db/db mice. In cultured hepatocytes, ATPSβ overexpression increased intracellular and extracellular ATP content, elevated cytosolic free calcium level and activated Akt independent of insulin. ATPSβ-induced increase in cytosolic free calcium and pAkt levels was attenuated by inhibition of P2 receptors. Notably, inhibition of Calmodulin (CaM) completely abolished ATPSβ-induced Akt activation in liver cells. Inhibition of P2 receptors or CaM blocked ATPSβ-induced nuclear exclusion of forkhead box O1 (FOXO1) in liver cells. In conclusion, a decrease in hepatic ATPSβ 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.
- Received July 12, 2013.
- Accepted November 21, 2013.
- © 2013 by the American Diabetes Association.
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