Tectorigenin enhances PDX1 expression and protects pancreatic β-cells by activating ERK and reducing ER stress

作者：Xinlei Yao, Kun Li, Liang Chen, Zilong Zhou, Jiao Wang, Shuyue Wang, Lei Liu, Chunlei Yu, Zhenbo Song, Yongli Bao, Lihua Zheng, Ying Sun, Guannan Wang, Yanxin Huang, Jingwen Yi, Luguo Sun, Yuxin Li · 发表于：Journal of Biological Chemistry · 年份：2020 · DOI：10.1074/jbc.ra120.012849 · 被引用次数：29 · 研究领域：Pancreatic function and diabetes、Adenosine and Purinergic Signaling、Endoplasmic Reticulum Stress and Disease

Pancreas/duodenum homeobox protein 1 (PDX1) is an important transcription factor that regulates islet β-cell proliferation, differentiation, and function. Reduced expression of PDX1 is thought to contribute to β-cell loss and dysfunction in diabetes. Thus, promoting PDX1 expression can be an effective strategy to preserve β-cell mass and function. Previously, we established a PDX1 promoter-dependent luciferase system to screen agents that can promote PDX1 expression. Natural compound tectorigenin (TG) was identified as a promising candidate that could enhance the activity of the promoter for the PDX1 gene. In this study, we first demonstrated that TG could promote the expression of PDX1 in β-cells via activating extracellular signal-related kinase (ERK), as indicated by increased phosphorylation of ERK; this effect was observed under either normal or glucotoxic/lipotoxic conditions. We then found that TG could suppress induced apoptosis and improved the viability of β-cells under glucotoxicity and lipotoxicity by activation of ERK and reduction of reactive oxygen species and endoplasmic reticulum (ER) stress. These effects held true in vivo as well: prophylactic or therapeutic use of TG could obviously inhibit ER stress and decrease islet β-cell apoptosis in the pancreas of mice given a high-fat/high-sucrose diet (HFHSD), thus dramatically maintaining or restoring β-cell mass and islet size, respectively. Accordingly, both prophylactic and therapeutic use of TG improved HFHSD...