Involvement of Estrogen Receptor-α in the Activation of Nrf2-Antioxidative Signaling Pathways by Silibinin in Pancreatic β-Cells

Silibinin exhibits antidiabetic potential by preserving the mass and function of pancreatic beta-cells through up-regulation of estrogen receptor-alpha (ERalpha) expression. However, the underlying protective mechanism of silibinin in pancreatic beta-cells is still unclear. In the current study, we sought to determine whether ERalpha acts as the target of silibinin for the modulation of antioxidative response in pancreatic beta-cells under high glucose and high fat conditions. Our in vivo study revealed that a 4-week oral administration of silibinin (100 mg/kg/day) decreased fasting blood glucose with a concurrent increase in levels of serum insulin in high-fat diet/streptozotocin- induced type 2 diabetic rats. Moreover, expression of ERalpha, NF-E2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) in pancreatic beta-cells in pancreatic islets was increased by silibinin treatment. Accordingly, silibinin (10 microM) elevated viability, insulin biosynthesis, and insulin secretion of high glucose/palmitate-treated INS-1 cells accompanied by increased expression of ERalpha, Nrf2, and HO-1 as well as decreased reactive oxygen species production in vitro. Treatment using an ERalpha antagonist (MPP) in INS-1 cells or silencing ERalpha expression in INS-1 and NIT-1 cells with siRNA abolished the protective effects of silibinin. Our study suggests that silibinin activates the Nrf2-antioxidative pathways in pancreatic beta-cells through regulation of ERalpha expression.