| The zinc transporter Slc39a5 controls glucose sensing and insulin secretion in pancreatic β-cells via Sirt1- and Pgc-1α-mediated regulation of Glut2 |
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| 引用本文： | Xinhui Wang,Hong Gao,Wenhui Wu,Enjun Xie,Yingying Yu,Xuyan He,Jin Li,Wanru Zheng,Xudong Wang,Xizhi Cao,Zhuoxian Meng,Ligong Chen,Junxia Min,Fudi Wang. The zinc transporter Slc39a5 controls glucose sensing and insulin secretion in pancreatic β-cells via Sirt1- and Pgc-1α-mediated regulation of Glut2[J]. 蛋白质与细胞, 2019, 10(6): 436-449. DOI: 10.1007/s13238-018-0580-1 |
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| 作者姓名： | Xinhui Wang Hong Gao Wenhui Wu Enjun Xie Yingying Yu Xuyan He Jin Li Wanru Zheng Xudong Wang Xizhi Cao Zhuoxian Meng Ligong Chen Junxia Min Fudi Wang |
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| 作者单位： | School of Public Health;School of Pharmaceutical Sciences;Department of Pathology and Pathophysiology |
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| 基金项目： | supported by research grants from the National Natural Science Foundation of China(31600953 to X.Wang;31530034 and 31330036 to F.Wang,31570791 and 91542205 to J.Min);the National Key R&D Program of China(2018YFA0507801 to J.Min and 2018YFA0507802 to F.Wang);the Zhejiang Provincial Natural Science Foundation of China(LQ15C110002 to X.Wang and LZ15H160002 to J.Min);the Nation Science and Technology Major Projects for Major New Drugs Innovation and Develop 2017ZX09101-005-004-002(L.Chen). |
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| 摘 要： | Zinc levels are high in pancreatic β-cells, and zinc is involved in the synthesis, processing and secretion of insulin in these cells. However, precisely how cellular zinc homeostasis is regulated in pancreatic β-cells is poorly understood. By screening the expression of 14 Slc39a metal importer family member genes, we found that the zinc transporter Slc39a5 is significantly downregulated in pancreatic β-cells in diabetic db/db mice, obese ob/ob mice and high-fat diet-fed mice. Moreover,β-cell-specific Slc39a5 knockout mice have impaired insulin secretion. In addition, Slc39a5-deficient pancreatic islets have reduced glucose tolerance accompanied by reduced expression of Pgc-1α and its downstream target gene Glut2. The down-regulation of Glut2 in Slc39a5-deficient islets was rescued using agonists of Sirt1, Pgc-1α and Ppar-γ. At the mechanistic level, we found that Slc39a5-mediated zinc influx induces Glut2 expression via Sirt1-mediated Pgc-1α activation. These findings suggest that Slc39a5 may serve as a possible therapeutic target for diabetes-related conditions.
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| 关 键 词： | ZINC ZINC TRANSPORTER PANCREATIC ISLETS β-cells insulin secretion |
The zinc transporter Slc39a5 controls glucose sensing and insulin secretion in pancreatic β-cells via Sirt1- and Pgc-1α-mediated regulation of Glut2 |
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| Xinhui Wang,Hong Gao,Wenhui Wu,Enjun Xie,Yingying Yu,Xuyan He,Jin Li,Wanru Zheng,Xudong Wang,Xizhi Cao,Zhuoxian Meng,Ligong Chen,Junxia Min,Fudi Wang. The zinc transporter Slc39a5 controls glucose sensing and insulin secretion in pancreatic β-cells via Sirt1- and Pgc-1α-mediated regulation of Glut2[J]. Protein & Cell, 2019, 10(6): 436-449. DOI: 10.1007/s13238-018-0580-1 |
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| Authors: | Xinhui Wang Hong Gao Wenhui Wu Enjun Xie Yingying Yu Xuyan He Jin Li Wanru Zheng Xudong Wang Xizhi Cao Zhuoxian Meng Ligong Chen Junxia Min Fudi Wang |
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| Abstract: | Zinc levels are high in pancreatic β-cells, and zinc is involved in the synthesis, processing and secretion of insulin in these cells. However, precisely how cellular zinc homeostasis is regulated in pancreatic β-cells is poorly understood. By screening the expression of 14 Slc39a metal importer family member genes, we found that the zinc transporter Slc39a5 is significantly downregulated in pancreatic β-cells in diabetic db/db mice, obese ob/ob mice and high-fat diet-fed mice. Moreover, β-cell-specific Slc39a5 knockout mice have impaired insulin secretion. In addition, Slc39a5-deficient pancreatic islets have reduced glucose tolerance accompanied by reduced expression of Pgc-1α and its downstream target gene Glut2. The down-regulation of Glut2 in Slc39a5-deficient islets was rescued using agonists of Sirt1, Pgc-1α and Ppar-γ. At the mechanistic level, we found that Slc39a5-mediated zinc influx induces Glut2 expression via Sirt1-mediated Pgc-1α activation. These findings suggest that Slc39a5 may serve as a possible therapeutic target for diabetes-related conditions. |
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| Keywords: | zinc zinc transporter pancreatic islets β-cells insulin secretion |
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