SREBP1c-PAX4 Axis Mediates Pancreatic β-Cell Compensatory Responses Upon Metabolic Stress

Abstract

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 β cells are largely unknown. In this study, we demonstrate that SREBP1c regulates β cell compensation under metabolic stress. SREBP1c expression level was augmented in pancreatic islets from obese and diabetic animals. In pancreatic β cells, SREBP1c activation promoted the expression of cell cycle genes and stimulated β cell proliferation through its novel target gene, PAX4. Compared to SREBP1c+/+ mice, SREBP1c– /– mice showed glucose intolerance with low insulin levels. Moreover, β 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. ollectively, these data suggest that pancreatic SREBP1c is a key player in mediating β cell compensatory responses in obesity.