title: Hepatic overexpression of ATP synthase β subunit activates PI3K/Akt pathway to ameliorate hyperglycemia of diabetic mice.
abstract: 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.
authors.affiliation: Department of Physiology and Pathophysiology, Key Laboratory of Molecular Cardiovascular Science, Peking (Beijing) University Health Science Center, Beijing, China.
authors.forename: Chunjiong
authors.initials: C
authors.lastname: Wang
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Chen
authors.forename: Sha
authors.initials: S
authors.lastname: Li
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Shi
authors.initials: S
authors.lastname: Jia
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Yujing
authors.initials: Y
authors.lastname: Chi
authors.forename: Yifei
authors.initials: Y
authors.lastname: Miao
authors.forename: Youfei
authors.initials: Y
authors.lastname: Guan
authors.forename: Jichun
authors.initials: J
authors.lastname: Yang
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005943:Gluconeogenesis; D056945:Hep G2 Cells; D006801:Humans; D006943:Hyperglycemia / Q000517:prevention & control*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D025261:Mitochondrial Proton-Translocating ATPases / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D015398:Signal Transduction; D013311:Streptozocin
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D013311:Streptozocin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C530489:ATP5b protein, mouse; D025261:Mitochondrial Proton-Translocating ATPases