title: Npas4 is a novel activity-regulated cytoprotective factor in pancreatic β-cells.
abstract: 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.
authors: Diabetes Research Group, Child and Family Research Institute, Vancouver, British Columbia, Canada.
authors: Paul V
authors: PV
authors: Sabatini
authors: Nicole A J
authors: NA
authors: Krentz
authors: Bader
authors: B
authors: Zarrouki
authors: Clara Y
authors: CY
authors: Westwell-Roper
authors: Cuilan
authors: C
authors: Nian
authors: Ryan A
authors: RA
authors: Uy
authors: A M James
authors: AM
authors: Shapiro
authors: Vincent
authors: V
authors: Poitout
authors: Francis C
authors: FC
authors: Lynn
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D019610:Cytoprotection / Q000187:drug effects / Q000235:genetics*; D004655:Emulsions / Q000494:pharmacology; D059865:Endoplasmic Reticulum Stress / Q000502:physiology; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D010743:Phospholipids / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D013024:Soybean Oil / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004655:Emulsions; D052216:Glucagon-Like Peptide 1; D005947:Glucose; D007328:Insulin; D010743:Phospholipids; D013024:Soybean Oil; C533005:Npas4 protein, mouse; C545823:soybean oil, phospholipid emulsion
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