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

摘要

SREBP1c is a key transcription factor for de novo lipo-genesis. Although SREBP1c is expressed in pancreatic islets, its physiological roles in pancreatic β-cells are largely unknown. In this study, we demonstrate that SREBPIc regulates β-cell compensation under metabolic stress. SREBP1c expression level was augmented in pancreatic islets from obese and diabetic animals. In pancreatic β-cells, SREBPIc activation promoted the expression of cell cycle genes and stimulated β-cell proliferation through its novel target gene, PAX4. Compared with 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 strep-tozotocin-induced diabetic animals. Collectively, these data suggest that pancreatic SREBP1c is a key player in mediating β-cell compensatory responses in obesity.