Npas4 Is a Novel Activity-Regulated Cytoprotective Factor in Pancreatic β-Cells
- Paul V. Sabatini1,2,
- Nicole A.J. Krentz1,2,
- Bader Zarrouki3,
- Clara Y. Westwell-Roper1,4,
- Cuilan Nian1,2,
- Ryan A. Uy1,
- A.M. James Shapiro5,
- Vincent Poitout3 and
- Francis C. Lynn1,2⇑
- 1Diabetes Research Group, Child and Family Research Institute, Vancouver, British Columbia, Canada
- 2Department of Surgery and Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada
- 3Montreal Diabetes Research Center, CRCHUM, and Department of Medicine, Université de Montréal, Montréal, Quebec, Canada
- 4Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
- 5Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
- Corresponding author: Francis Lynn,
Cellular homeostasis requires intrinsic sensing mechanisms to temper function in the face of prolonged activity. In the pancreatic β-cell, glucose is likely a physiological trigger that activates an adaptive response to stimulation, thereby maintaining cellular homeostasis. Immediate early genes (IEGs) are activated as a first line of defense in cellular homeostasis and are largely responsible for transmitting an environmental cue to a cellular response. Here we examine the regulation and function of the novel β-cell IEG, neuronal PAS domain protein 4 (Npas4). Using MIN6 cells, mouse and human islets, as well as in vivo infusions, we demonstrate that Npas4 is expressed within pancreatic islets and is upregulated by β-cell depolarizing agents. Npas4 tempers β-cell function through a direct inhibitory interaction with the insulin promoter and by blocking the potentiating effects of GLP-1 without significantly reducing glucose-stimulated secretion. Finally, Npas4 expression is induced by classical endoplasmic reticulum (ER) stressors and can prevent thapsigargin- and palmitate-induced dysfunction and cell death. These results suggest that Npas4 is a key activity-dependent regulator that improves β-cell efficiency in the face of stress. We posit that Npas4 could be a novel therapeutic target in type 2 diabetes that could both reduce ER stress and cell death and maintain basal cell function.
- Received November 5, 2012.
- Accepted March 28, 2013.
- © 2013 by the American Diabetes Association.
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