2193-P: SREBP1c-PAX4 Axis Mediates Pancreatic Beta-Cell Compensatory Responses upon Metabolic Stress

Sterol responsive element-binding protein 1c (SREBP1c) is a key transcription factor for de novo lipogenesis. Although SREBP1c is expressed in pancreatic islets, its physiological roles in pancreatic beta cells are largely unknown. In this study, we demonstrate that SREBP1c regulates beta cell compensation under metabolic stress. SREBP1c expression level was augmented in pancreatic islets from obese and diabetic animals. In pancreatic beta cells, SREBP1c activation promoted the expression of cell cycle genes and stimulated beta cell proliferation through its novel target gene, PAX4. Compared to SREBP1c+/+ mice, SREBP1c-/- mice showed glucose intolerance with low insulin levels. Moreover, beta cells from SREBP1c-/- mice exhibited reduced capacity to proliferate and secrete insulin. Conversely, transplantation of SREBP1c overexpressing islets restored insulin levels and relieved hyperglycemia in streptozotocin-induced diabetic animals. Collectively, these data suggest that pancreatic SREBP1c is a key player in mediating beta cell compensatory responses in obesity.