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

Abstract

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, <i>PAX4</i> Compared with <i>SREBP1c^+/+</i> mice, <i>SREBP1c^-/-</i> mice showed glucose intolerance with low insulin levels. Moreover, β-cells from <i>SREBP1c^-/-</i> 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 β-cell compensatory responses in obesity.