The zinc transporter Slc39a5 controls glucose sensing and insulin secretion in pancreatic β-cells via Sirt1- and Pgc-1α-mediated regulation of Glut2.
10.1007/s13238-018-0580-1
- Author:
Xinhui WANG
1
;
Hong GAO
1
;
Wenhui WU
1
;
Enjun XIE
1
;
Yingying YU
1
;
Xuyan HE
1
;
Jin LI
1
;
Wanru ZHENG
1
;
Xudong WANG
1
;
Xizhi CAO
2
;
Zhuoxian MENG
3
;
Ligong CHEN
4
;
Junxia MIN
5
;
Fudi WANG
6
Author Information
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.
4. 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. ligongchen@tsinghua.edu.edu.
5. School of Public Health, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China. junxiamin@zju.edu.cn.
6. School of Public Health, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China. fwang@zju.edu.cn.
- Publication Type:Journal Article
- Keywords:
insulin secretion;
pancreatic islets;
zinc;
zinc transporter;
β-cells
- From:
Protein & Cell
2019;10(6):436-449
- CountryChina
- Language:English
-
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 down-regulated 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.
