(-)-Epigallocatechin 3-gallate protects pancreatic β-cell against excessive autophagy-induced injury through promoting FTO degradation
Yixue Shao, Yuhan Zhang, Suyun Zou, Jianan Wang, Xirui Li, Miaozhen Qin, Liangjun Sun, Wenyue Yin, Xiaoai Chang, Shusen Wang, Han Xiao, Tijun Wu, Fang Chen
Abstract
Excessive macroautophagy/autophagy leads to pancreatic β-cell failure that contributes to the development of diabetes. Our previous study proved that the occurrence of deleterious hyperactive autophagy attributes to glucolipotoxicity-induced NR3C1 activation. Here, we explored the potential protective effects of (-)-epigallocatechin 3-gallate (EGCG) on β-cell-specific NR3C1 overexpression mice in vivo and NR3C1-enhanced β cells in vitro. We showed that EGCG protects pancreatic β cells against NR3C1 enhancement-induced failure through inhibiting excessive autophagy. RNA demethylase FTO (FTO alpha-ketoglutarate dependent dioxygenase) caused diminished m6A modifications on mRNAs of three pro-oxidant genes (Tlr4, Rela, Src) and, hence, oxidative stress occurs; by contrast, EGCG promotes FTO degradation by the ubiquitin-proteasome system in NR3C1-enhanced β cells, which alleviates oxidative stress, and thereby prevents excessive autophagy. Moreover, FTO overexpression abolishes the beneficial effects of EGCG on β cells against NR3C1 enhancement-induced damage. Collectively, our results demonstrate that EGCG protects pancreatic β cells against NR3C1 enhancement-induced excessive autophagy through suppressing FTO-stimulated oxidative stress, which provides novel insights into the mechanisms for the anti-diabetic effect of EGCG.