Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 294, Issue 13, Pages 4889-4897Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA118.005135
Keywords
beta-cell; diabetes; apoptosis; nuclear receptor; cytokine; pancreas; insulin; Nr4a
Categories
Funding
- Alberta Diabetes Foundation
- Canadian Institutes of Health Research
- Natural Sciences and Engineering Research Council of Canada
- Wallonie-Bruxelles International
- Alberta Innovates Health Solutions
- Canadian Institutes of Health Research New Investigator Award
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The Nr4a subfamily of nuclear receptor comprises three members in mammalian cells: Nur77/Nr4a1, Nurr1/Nr4a2, and Nor1/Nr4a3. Nr4a proteins play key roles in the regulation of glucose homeostasis in peripheral metabolic tissues. However, their biological functions in -cells remain relatively uncharacterized. Here we sought to investigate the potential role of Nor1 in the regulation of -cell mass and, in particular, beta-cell survival/apoptosis. We used histological analysis to examine the consequences of genetic deletion of either Nur77 and Nor1 on beta-cell mass, investigated the expression patterns of Nr4as in human islets and INS cells and performed gain- and loss-of-function experiments to further characterize the role of Nor1 in beta-cell apoptosis. Surprisingly, Nor1 knockout mice displayed increased beta-cell mass, whereas mice with genetic deletion of Nur77 did not exhibit any significant differences compared with their WT littermates. The increase in beta-cell mass in Nor1 knockout mice was accompanied by improved glucose tolerance. A gene expression study performed in both human islets and INS cells revealed that Nor1 expression is significantly increased by pro-inflammatory cytokines and, to a lesser extent, by elevated concentrations of glucose. Nor1 overexpression in both INS and human islet cells caused apoptosis, whereas siRNA-mediated Nor1 knockdown prevented cytokine-induced beta-cell death. Finally, Nor1 expression was up-regulated in islets of individuals with type 2 diabetes. Altogether, our results uncover that Nor1 negatively regulates beta-cell mass. Nor1 represents a promising molecular target in diabetes treatment to prevent beta-cell destruction.
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