| First Author | Close AF | Year | 2019 |
| Journal | J Biol Chem | Volume | 294 |
| Issue | 13 | Pages | 4889-4897 |
| PubMed ID | 30696767 | Mgi Jnum | J:279591 |
| Mgi Id | MGI:6316538 | Doi | 10.1074/jbc.RA118.005135 |
| Citation | Close AF, et al. (2019) The orphan nuclear receptor Nor1/Nr4a3 is a negative regulator of beta-cell mass. J Biol Chem 294(13):4889-4897 |
| abstractText | 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 beta-cells remain relatively uncharacterized. Here we sought to investigate the potential role of Nor1 in the regulation of beta-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. |
