Location: Children's Nutrition Research CenterTitle: SCP4 promotes gluconeogenesis through Fox01/3a dephosphorylation
|Cao, Jin - Baylor College Of Medicine|
|Yu, Yi - Baylor College Of Medicine|
|Zhang, Zhengmao - Baylor College Of Medicine|
|Chen, Xi - Baylor College Of Medicine|
|Hu, Zhaoyong - Baylor College Of Medicine|
|Tong, Qiang - Children'S Nutrition Research Center (CNRC)|
|Chang, Jiang - Texas A&M University Health Science Center|
|Feng, Xin-hua - Baylor College Of Medicine|
|Lin, Xia - Baylor College Of Medicine|
Submitted to: Diabetes
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/21/2017
Publication Date: 1/5/2018
Citation: Cao, J., Yu, Y., Zhang, Z., Chen, X., Hu, Z., Tong, Q., Chang, J., Feng, X., Lin, X. 2018. SCP4 promotes gluconeogenesis through Fox01/3a dephosphorylation. Diabetes. 67(1):46-57.
Interpretive Summary: FoxO proteins regulate many cellular processes, including liver glucose production. Modifying a FoxO protein by adding phospho groups to it (phosphorylation) is a key event that determines FoxO's cellular location and FoxO's activity. Phosphorylation of FoxO negatively regulated its activity by keeping FoxO protein outside of the nucleus, where it needs to function. In this study, we discovered an enzyme called SCP4 to be a phosphatase of FoxO proteins, which means that SCP4 can remove the phospho group from its target protein, in this case the FoxO protein. By doing so, SCP4 promotes FoxO proteins to enter the nucleus and to activate PEPCK1 and G6PC genes, two key enzymes involved in liver glucose synthesis. Therefore, increasing the expression of SCP4 increases liver cell glucose production, whereas suppressing SCP4 inhibits glucose production. Moreover, we demonstrated that deleting the SCP4 gene in mice led to low blood glucose in newborn mice. We also found that SCP4 expression is induced by glucose deprivation in vitro and in vivo and SCP4 level is elevated in obese mice caused by genetic or dietary manipulations. Thus, our findings provide experimental evidence that SCP4 regulates liver glucose production. Therefore, SCP4 inhibition might be used as a novel prevention and treatment method for type 2 diabetes.
Technical Abstract: FoxO1 and FoxO3a (collectively FoxO1/3a) proteins regulate a wide array of cellular processes, including hepatic gluconeogenesis. Phosphorylation of FoxO1/3a is a key event that determines its subcellular location and transcriptional activity. During glucose synthesis, the activity of FoxO1/3a is negatively regulated by Akt-mediated phosphorylation, which leads to the cytoplasmic retention of FoxO1/3a. However, the nuclear phosphatase that directly regulates FoxO1/3a remains to be identified. In this study, we discovered a nuclear phosphatase, SCP4/CTDSPL2 (SCP4), that dephosphorylated FoxO1/3a and promoted FoxO1/3a transcription activity. We found that SCP4 enhanced the transcription of FoxO1/3a target genes encoding PEPCK1 and G6PC, key enzymes in hepatic gluconeogenesis. Ectopic expression of SCP4 increased, while knockdown of SCP4 inhibited, glucose production. Moreover, we demonstrated that gene ablation of SCP4 led to hypoglycemia in neonatal mice. Consistent with the positive role of SCP4 in gluconeogenesis, expression of SCP4 was regulated under pathophysiological conditions. SCP4 expression was induced by glucose deprivation in vitro and in vivo and was elevated in obese mice caused by genetic (Avy) and dietary (high-fat) changes. Thus, our findings provided experimental evidence that SCP4 regulates hepatic gluconeogenesis and could serve as a potential target for the prevention and treatment of diet-induced glucose intolerance and type 2 diabetes.