W2476 represses TXNIP transcription via dephosphorylation of FOXO1 at Ser319
W2476 represses TXNIP transcription via dephosphorylation of FOXO1 at Ser319
复制标题
DOI：
10.1111/cbdd.13828
复制
发表时间：
2021-02-16
影响因子：
3
通讯作者：
Wang, Ming-Wei
中科院分区：
文献类型：
--
作者：
Zhong, Li;Liu, Qing;Wang, Ming-Wei
硫氧还蛋白相互作用蛋白 (TXNIP) 过度表达与 2 型糖尿病的发病机制有关。先前的研究表明，一种小分子化合物（W2476）能够通过抑制TXNIP信号通路来改善糖尿病小鼠的β细胞功能障碍并发挥治疗作用。因此，使用染色质免疫沉淀方法研究了 W2476 对 TXNIP 转录的影响。研究发现，W2476 促进叉头框 O1 转录因子 (FOXO1) 与与 ChoRE 结合蛋白 (ChREBP)/Mlx 相互作用蛋白样 (Mlx) 复合物相关的碳水化合物反应元件 (ChoRE) 序列竞争性结合。这种相互作用阻碍了组蛋白乙酰转移酶 p300 的附着，并减少了 TXNIP 启动子上的组蛋白 H4 乙酰化，从而导致 TXNIP 转录减少。
Thioredoxin-interacting protein (TXNIP) overexpression is implicated in the pathogenesis of type 2 diabetes. Previous studies have shown that a small molecule compound (W2476) was able to improve beta-cell dysfunction and exert therapeutic effects in diabetic mice via repression of TXNIP signaling pathway. The impact of W2476 on TXNIP transcription was thus investigated using the chromatin immunoprecipitation method. It was found that W2476 promotes competitive binding of forkhead box O1 transcription factor (FOXO1) to the carbohydrate response element (ChoRE) sequence associated with ChoRE-binding protein (ChREBP)/Mlx interacting protein-like(Mlx) complexes. This interaction hinders the attachment of histone acetyltransferase p300 and reduces histone H4 acetylation on the TXNIP promoter, leading to decreasing TXNIP transcription.