Regulation of Pancreatic β-cell Life and Death in the Context of Type 2 Diabetes: Study of the Potential Implication of the Orphan Nuclear Receptor NR4A3/Nor1 and the NZF Transcription Factor ST18.

• Author / Creator

  Close, Anne-Françoise J

• Background: The insulin-secreting pancreatic beta-cell plays a central role in the maintenance of glucose homeostasis and in the pathogenesis of both type 1 and type 2 diabetes mellitus. In both cases, production of pro-inflammatory cytokines causes beta-cell apoptosis, which results in the progressive deterioration of beta-cell mass and function. Thus, it is important to understand the molecular mechanisms underlying the regulation of beta-cell “life and death” as this could lead to the development of new therapeutic options. Previous studies have identified Nor1 as a potentially important gene in the pathogenesis of diabetes. The Nor1 gene encodes a nuclear receptor of the Nr4a family. Whereas Nor1 has been extensively studied in other tissues, its biological roles in the beta-cell remain relatively unexplored. Aim: We therefore sought to investigate the expression and potential role of Nor1 in the regulation of pancreatic beta-cell mass. Results: Pro-inflammatory cytokines produced a significant up-regulation of Nor1 mRNA and protein levels in beta-cells. Interestingly, this effect seemed specific to Nor1, as other members of the Nr4a family were less affected by cytokines. Overexpression of Nor1 induced beta-cell apoptosis. Conversely, siRNA-mediated silencing of Nor1 abolished cytokine-induced apoptosis. Nor1-Knockout(KO) mice presented an increased beta-cell mass and better glucose tolerance compared to wild type animals. Surprisingly, we detected a rapid translocation of Nor1 to the mitochondria in beta-cells exposed to cytokines. In addition, our genomic study revealed that Nor1 down-regulated the expression of genes encoded by the mitochondrial genome. This prompted us to further investigate the role of Nor1 at the mitochondria. Nor1 reduced glucose oxidation and ATP production in beta-cells. Consistently, Nor1 also modulated mitochondrial membrane potential. Electron microscopy images revealed that Nor1 induced mitochondrial fractionation and increased mitophagy. Conclusion: Our study characterizes Nor1 as a mediator of cytokine-induced beta-cell death. We thereby demonstrate a critical role for Nor1 in the regulation of beta-cell mass and identify Nor1 as a new molecular target for the treatment of diabetes.

• Subjects / Keywords

  • Beta-cell
  • Transcriptional regulation
  • Apoptosis
  • Mitochondria

• Graduation date

  Fall 2017

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R33F4M242

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.