CEBPA Overexpression Enhances -Cell Proliferation and Survival

Simple Summary The objective of this study was to define the role of the transcription factor CEBPA on pancreatic beta cell function, replication, and survival. We have previously shown that Nkx6.1 induces CEBPA expression, and that this correlates with increased beta cell proliferation, insulin secretion, and cell survival. We show that CEBPA can induce beta cell proliferation, but of greater interest, it is able to protect beta cells from glucolipotoxic damage that causes endoplasmic reticulum stress that results in cell death. Our findings suggest that modulation of CEBPA activity could be used as a treatment to protect and expand a patient's beta cells.Abstract A commonality between type 1 and type 2 diabetes is the decline in functional beta-cell mass. The transcription factor Nkx6.1 regulates beta-cell development and is integral for proper beta-cell function. We have previously demonstrated that Nkx6.1 depends on c-Fos mediated upregulation and the nuclear hormone receptors Nr4a1 and Nr4a3 to increase beta-cell insulin secretion, survival, and replication. Here, we demonstrate that Nkx6.1 overexpression results in upregulation of the bZip transcription factor CEBPA and that CEBPA expression is independent of c-Fos regulation. In turn, CEBPA overexpression is sufficient to enhance INS-1 832/13 beta-cell and primary rat islet proliferation. CEBPA overexpression also increases the survival of beta-cells treated with thapsigargin. We demonstrate that increased survival in response to ER stress corresponds with changes in expression of various genes involved in the unfolded protein response, including decreased Ire1a expression. These data show that CEBPA is sufficient to enhance functional beta-cell mass by increasing beta-cell proliferation and modulating the unfolded protein response.