The National Center for Drug Screening, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai, China.
University of Chinese Academy of Sciences, Beijing, China.
Chem Biol Drug Des. 2021 May;97(5):1089-1099. doi: 10.1111/cbdd.13828. Epub 2021 Feb 16.
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 β-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.
硫氧还蛋白相互作用蛋白（TXNIP）的过表达与 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细胞功能并发挥治疗作用。因此，使用染色质免疫沉淀法研究了 W2476 对 TXNIP 转录的影响。结果发现，W2476 促进了叉头框 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）序列的竞争性结合。这种相互作用阻碍了组蛋白乙酰转移酶 p300 的附着，并降低了 TXNIP 启动子上的组蛋白 H4 乙酰化，从而导致 TXNIP 转录减少。
