Celastrol targets the ChREBP-TXNIP axis to ameliorates type 2 diabetes mellitus

作者全名："Zhou, Duanfang; Li, Xiaoli; Xiao, Xiaoqiu; Wang, Gang; Chen, Bo; Song, Yi; Liu, Xu; He, Qichen; Zhang, Huan; Wu, Qiuya; Zhang, Limei; Wu, Lihong; Shen, Zhengze; Hassan, Moustapha; Zhao, Ying; Zhou, Weiying"

作者地址："[Zhou, Duanfang; Li, Xiaoli; Wang, Gang; Chen, Bo; Song, Yi; Liu, Xu; He, Qichen; Zhang, Huan; Wu, Qiuya; Zhang, Limei; Wu, Lihong; Zhou, Weiying] Chongqing Med Univ, Coll Pharm, Dept Pharmacol, Chongqing, Peoples R China; [Zhou, Duanfang; Li, Xiaoli; Wang, Gang; Chen, Bo; Song, Yi; Liu, Xu; He, Qichen; Zhang, Huan; Wu, Qiuya; Zhang, Limei; Wu, Lihong; Zhou, Weiying] Chongqing Key Lab Drug Metab, Chongqing, Peoples R China; [Li, Xiaoli; Zhou, Weiying] Key Lab Biochem & Mol Pharmacol Chongqing, Chongqing, Peoples R China; [Zhou, Duanfang] Chongqing Med Univ, Dept Pharm, Women & Childrens Hosp, Chongqing, Peoples R China; [Xiao, Xiaoqiu] Chongqing Med Univ, Affiliated Hosp 1, Chongqing Key Lab Translat Med Major Metab Dis, Chongqing, Peoples R China; [Shen, Zhengze] Chongqing Med Univ, Dept Pharm, Yongchuan Hosp, Chongqing, Peoples R China; [Hassan, Moustapha; Zhao, Ying] Karolinska Inst, Dept Lab Med, Div Biomol & Cellular Med BCM, Expt Canc Med, Solna, Sweden; [Zhou, Weiying] Chongqing Med Univ, Coll Pharm, 1 Yixueyuan Rd, Chongqing 400016, Peoples R China"

通信作者："Zhou, WY (通讯作者)，Chongqing Med Univ, Coll Pharm, 1 Yixueyuan Rd, Chongqing 400016, Peoples R China."

来源：PHYTOMEDICINE

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:000918037500001

JCR分区：Q1

影响因子：7.9

年份：2023

卷号：110

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Celastrol; ChREBP; Diabetes; Metabolism; TXNIP

摘要："Backgrounds: Thioredoxin-interacting protein (TXNIP) plays a pivotal role in regulation of blood glucose ho-meostasis and is an emerging therapeutic target in diabetes and its complications. Celastrol, a pentacyclic tri-terpene extracted from the roots of Tripterygium wilfordii Hook F, can reduce insulin resistance and improve diabetic complications.Purpose: This study aimed to untangle the mechanism of celastrol in ameliorating type 2 diabetes (T2DM) and evaluate its potential benefits as an anti-diabetic agent.Methods: db/db mice was used to evaluate the hypoglycemic effect of celastrol in vivo; Enzyme-linked immu-nosorbent assay (ELISA) and 2-NBDG assay were used to detect the effect of celastrol on insulin secretion and glucose uptake in cells; Western blotting, quantitative reverse transcription PCR (RT-qPCR) and immunohisto-logical staining were used to examine effect of celastrol on the expression of TXNIP and the carbohydrate response element-binding protein (ChREBP). Molecular docking, cellular thermal shift assay (CETSA), drug af-finity responsive targets stability assay (DARTS) and mass spectrometry were used to test the direct binding between celastrol and ChREBP. Loss-and gain-of-function studies further confirmed the role of ChREBP and TXNIP in celastrol-mediated amelioration of T2DM.Results: Celastrol treatment significantly reduced blood glucose level, body weight and food intake, and improved glucose tolerance in db/db mice. Moreover, celastrol promoted insulin secretion and improved glucose ho-meostasis. Mechanistically, celastrol directly bound to ChREBP, a primary transcriptional factor upregulating TXNIP expression. By binding to ChREBP, celastrol inhibited its nuclear translocation and promoted its pro-teasomal degradation, thereby repressing TXNIP transcription and ultimately ameliorating T2DM through breaking the vicious cycle of hyperglycemia deterioration and TXNIP overexpression.Conclusion: Celastrol ameliorates T2DM through targeting ChREBP-TXNIP aix. Our study identified ChREBP as a new direct molecular target of celastrol and revealed a novel mechanism for celastrol-mediated amelioration of T2DM, which provides experimental evidence for its possible use in the treatment of T2DM and new insight into diabetes drug development for targeting TXNIP."

基金机构：National Natural Science Foundation of China [82173869]; Basic Research and Frontier Exploration Project of Chongqing Science and Technology Commission [cstc2021ycjh-bgzxm0133]; Innovation research group in Colleges and Universities Program of Chongqing Municipal Education Commission [CXQT20012]; High-level Young Scientific and Technological Talent Cultivation Program of Chongqing Medical University

基金资助正文："Funding This work was supported by grants from the National Natural Science Foundation of China (No. 82173869) , the Basic Research and Frontier Exploration Project of Chongqing Science and Technology Commission (cstc2021ycjh-bgzxm0133) , Innovation research group in Colleges and Universities Program of Chongqing Municipal Education Commission (No. CXQT20012) and High-level Young Scientific and Technological Talent Cultivation Program of Chongqing Medical University."