Acute cytokine-mediated downregulation of the zinc transporter ZnT8 alters pancreatic beta-cell function.
Genetic studies suggest that Zn transporters such as ZnT8 play a role in insulin secretion by pancreatic beta-cells; however, little is known about the dynamic roles of Zn trafficking pathways on beta-cell physiology. To test the acute effects of the inflammatory cytokines interleukin 1 beta (IL1 beta) and tumor necrosis factor alpha (TNFalpha) on Zn homeostasis, the mRNA expression profile of Zn transporters of the ZnT and ZIP families was examined. Exposure of MIN6 cells or primary murine islets to IL1 beta or TNFalpha altered the mRNA expression profile of Zn transporters; most notable was decreased ZnT8 mRNA levels. siRNA-mediated gene knockdown was used to examine the effects of decreased ZnT8 expression in primary dispersed murine islet cells from C57/BL6 mice and MIN6 cells. ZnT8 knockdown in these murine islets led to reduced glucose stimulated insulin secretion without altering the total cellular insulin content or cell viability at normal or supraphysiological Zn concentrations. The labile Zn content determined by flow cytometry after loading with the Zn-specific sensor FluoZin-3 AM was decreased in MIN6 cells following ZnT8 knockdown or IL1 beta treatment. These results suggest that an acute decrease in ZnT8 levels impairs beta-cell function and Zn homeostasis, and may contribute to inflammatory cytokine-induced alterations in beta-cell function.
Division of Endocrinology, Metabolism and Molecular Medicine, Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Tarry 15-755, Chicago, Illinois 60611, USA. m-muayed@northwestern.edu
Malek
M
El Muayed
Liana K
LK
Billings
Meera R
MR
Raja
Xiaomin
X
Zhang
Paul J
PJ
Park
Marsha V
MV
Newman
Dixon B
DB
Kaufman
Thomas V
TV
O'Halloran
William L
WL
Lowe
D000818:Animals; D015153:Blotting, Western; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D018929:Cell Culture Techniques; D002470:Cell Survival; D015536:Down-Regulation / Q000187:drug effects; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D000075703:Zinc Transporter 8
D027682:Cation Transport Proteins; D007328:Insulin; D053583:Interleukin-1beta; D012333:RNA, Messenger; C516348:Slc30a8 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D000075703:Zinc Transporter 8