Involvement of Estrogen Receptor-α in the Activation of Nrf2-Antioxidative Signaling Pathways by Silibinin in Pancreatic β-Cells
Chun Chu1,†, Xiang Gao2,†, Xiang Li3, Xiaoying Zhang4, Ruixin Ma4, Ying Jia4, Dahong Li2, Dongkai Wang1,* and Fanxing Xu5,*
1Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning,
2Department of Natural Products Chemistry, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning,
3Qiqihaer Middle School, Qiqihaer 161099, Heilongjiang,
4Department of Food Quality and Safety, Faculty of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning,
5Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning, China
*E-mail: (Wang D), (Xu F)
Tel: +86-24-43520529 (Wang D), +86-24-2398-6973 (Xu F)
Fax: +86-24-43520529 (Wang D), +86-24-2398-6973 (Xu F)

The first two authors contributed equally to this work.
Received: April 28, 2019; Revised: August 18, 2019; Accepted: September 4, 2019; Published online: October 25, 2019.
© The Korean Society of Applied Pharmacology. All rights reserved.

Silibinin exhibits antidiabetic potential by preserving the mass and function of pancreatic β-cells through up-regulation of estrogen receptor-α (ERα) expression. However, the underlying protective mechanism of silibinin in pancreatic β-cells is still unclear. In the current study, we sought to determine whether ERα acts as the target of silibinin for the modulation of antioxidative response in pancreatic β-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 ERα, NF-E2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) in pancreatic β-cells in pancreatic islets was increased by silibinin treatment. Accordingly, silibinin (10 µM) elevated viability, insulin biosynthesis, and insulin secretion of high glucose/palmitate-treated INS-1 cells accompanied by increased expression of ERα, Nrf2, and HO-1 as well as decreased reactive oxygen species production in vitro. Treatment using an ERα antagonist (MPP) in INS-1 cells or silencing ERα 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 β-cells through regulation of ERα expression.
Keywords: Diabetes mellitus, Silibinin, Pancreatic β-cell, Estrogen receptor-α, Antioxidative response

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