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 

作者机构：School of Public Health The First Affiliated Hospital Institute of Translational Medicine Zhejiang University School of Medicine Hangzhou 310058 China 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 Department of Pathology and Pathophysiology Key Laboratory of Disease Proteomics of Zhejiang Province Zhejiang University School of Medicine Hangzhou 310058 China 

出 版 物：《Protein & Cell》 (蛋白质与细胞（英文版）)

年 卷 期：2019年第10卷第6期

页      面：436-449页

核心收录：

学科分类：08[工学] 0835[工学-软件工程] 081202[工学-计算机软件与理论] 0812[工学-计算机科学与技术（可授工学、理学学位）] 

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) 

主　　题：zinc zinc transporter pancreatic islets β-cells insulin secretion 

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.