The zinc transporter Slc39a5 controls glucose sensing and insulin secretion in pancreatic β-cells via Sirt1- and Pgc-1α-mediated regulation of Glut2  

作　　者：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 

机构地区：[1]School of Public Health, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China [2]School of Pharmaceutical Sciences, State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China [3]Department of Pathology and Pathophysiology, Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou 310058, China

出　　处：《Protein & Cell》2019年第6期436-449,共14页蛋白质与细胞（英文版）

基　　金：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).

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.

关 键 词：ZINC ZINC TRANSPORTER PANCREATIC ISLETS β-cells insulin secretion 

分 类 号：TP311.56[自动化与计算机技术—计算机软件与理论]