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⇑
- 1Department of Physiology and Pathophysiology, Key Laboratory of Molecular Cardiovascular Science, Peking (Beijing) University Health Science Center, Beijing, China
- 2Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
- 3Department of Laboratory Medicine, Peking University Third Hospital, Beijing, China
- 4Shenzhen University Diabetes Center, Shenzhen University Health Science Center, Shenzhen, China
- Corresponding author: Jichun Yang, .
C.W., Z.C., and S.L. 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. ATPSβ expression and ATP content were both reduced in the livers of type 1 and type 2 diabetic mice. Hepatic overexpression of ATPSβ elevated cellular ATP content and ameliorated hyperglycemia of streptozocin-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 the cytosolic free calcium level, and activated Akt independent of insulin. The 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 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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-1096/-/DC1.
- Received July 12, 2013.
- Accepted November 21, 2013.
- © 2014 by the American Diabetes Association.
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