HS218 as an FXR antagonist suppresses gluconeogenesis by inhibiting FXR binding to PGC-1 alpha promoter
文献类型：期刊论文
| 作者 | Xu, Xin1,2; Shi, Xiaofan1,2; Chen, Yidi3; Zhou, Tingting1,2; Wang, Jiaying3; Xu, Xing4; Chen, Lili1,2 ; Hu, Lihong1,2,3; Shen, Xu1,2,3
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| 刊名 | METABOLISM-CLINICAL AND EXPERIMENTAL
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| 出版日期 | 2018-08-01 |
| 卷号 | 85页码:126-138 |
| 关键词 | T2DM Gluconeogenesis FXR antagonist PGC-1 alpha Drug lead compound |
| ISSN号 | 0026-0495 |
| DOI | 10.1016/j.metabol.2018.03.016 |
| 通讯作者 | Hu, Lihong(lhhu@simm.ac.cn) ; Shen, Xu(xshen@njucm.edu.cn) |
| 英文摘要 | Introduction: Famesoid X receptor (FXR) as a member of nuclear receptor is tightly associated with glucose metabolism. Accumulated evidence has addressed the potential of FXR antagonist in the treatment of type 2 diabetes mellitus (T2DM), although the related mechanisms remain unclear. Here, we determined a specific FXR antagonist HS218 (N-benzyl-N-(3-(tert-butyl)-4-hydroxyphenyl)-2,4-dichlorobenzamide), which exhibited high activities in suppressing gluconeogenesis and ameliorating glucose homeostasis in db/db and HFD/STZ-induced T2DM mice. We would like to investigate the mechanisms underlying FXR antagonism in the regulation of gluconeogenesis by using HS218 as a probe. Methods: HS218 was evaluated by glucose output assay. Binding affinity of HS218 to the ligand binding domain of FXR (FXR-LBD) was detected by Surface Plasmon Resonance (SPR) technology-based Biacore and fluorescence quenching assays. Mammalian one-hybrid and transactivation assays were carried out to detect the antagonistic effect of HS218 on FXR. Real-time PCR assay was performed to measure the expressions of FXR-target and gluconeogenic genes. Anti-diabetic efficiencies of HS218 were determined in db/db and HFD/STZ-induced T2DM mice. Assays by promoter 5'-deletion analysis and Chromatin immunoprecipitation (ChIP) were performed to detect the binding of FXR to peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) promoter. Western blot assay was used to determine the protein level in either cells or the liver tissues of mice. Results: We determined that HS218 as a new FXR specific antagonist could FXR-dependently suppress gluconeogenesis in mouse primary hepatocytes, and effectively improve glucose homeostasis in db/db and HFD/STZ-induced T2DM mice. HS218 decreased gluconeogenesis by inhibiting the FXR-induced increase in the promoter activity of the key gluconeogenic gene PGC-1 alpha, leading to the repression of PGC-1 alpha and its target gene peroxisome proliferator-activated receptor alpha (PPAR alpha). Conclusions: To our knowledge, our work might be the first report on the mechanism underlying FXR antagonist in the regulation of gluconeogenesis, and all results have also highlighted the potential of HS218 in the treatment of T2DM. (C) 2018 Elsevier Inc. All rights reserved. |
| WOS关键词 | FARNESOID-X-RECEPTOR ; NUCLEAR RECEPTOR ; CARBOHYDRATE-METABOLISM ; HEPATIC GLUCONEOGENESIS ; BILE-ACIDS ; ALPHA ; IDENTIFICATION ; ACTIVATION ; EXPRESSION ; PROTECTS |
| 资助项目 | National Natural Science Foundation of China[81473141] ; National Natural Science Foundation of China[81373462] ; NSFC-TRF collaboration projects[NSFC81561148011] ; Institute for Drug Discovery and Development, Chinese Academy of Sciences[CASIMM0120162023] ; Key Laboratory of Receptor Research of the Chinese Academy of Sciences[SIMM1606YZZ-04] ; National Natural Science Foundation for Young Scientists of China[81703806] ; Personalized Medicines: Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12040313] |
| WOS研究方向 | Endocrinology & Metabolism |
| 语种 | 英语 |
| WOS记录号 | WOS:000454746400013 |
| 出版者 | W B SAUNDERS CO-ELSEVIER INC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/290841]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Hu, Lihong; Shen, Xu |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Key Lab Receptor Research, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 3.Nanjing Univ Chinese Med, Sch Med & Life Sci, State Key Lab Cultivat Base TCM Qual & Efficacy, 138 Xianlin Rd, Nanjing 210023, Jiangsu, Peoples R China 4.Shanghai Jiao Tong Univ, Shanghai Inst Traumatol & Orthopaed, Shanghai Ruijin Hosp, Shanghai Key Lab Bone & Joint Dis,Sch Med, Shanghai 200025, Peoples R China |
| 推荐引用方式 GB/T 7714 | Xu, Xin,Shi, Xiaofan,Chen, Yidi,et al. HS218 as an FXR antagonist suppresses gluconeogenesis by inhibiting FXR binding to PGC-1 alpha promoter[J]. METABOLISM-CLINICAL AND EXPERIMENTAL,2018,85:126-138. |
| APA | Xu, Xin.,Shi, Xiaofan.,Chen, Yidi.,Zhou, Tingting.,Wang, Jiaying.,...&Shen, Xu.(2018).HS218 as an FXR antagonist suppresses gluconeogenesis by inhibiting FXR binding to PGC-1 alpha promoter.METABOLISM-CLINICAL AND EXPERIMENTAL,85,126-138. |
| MLA | Xu, Xin,et al."HS218 as an FXR antagonist suppresses gluconeogenesis by inhibiting FXR binding to PGC-1 alpha promoter".METABOLISM-CLINICAL AND EXPERIMENTAL 85(2018):126-138. |
入库方式： OAI收割
来源：上海药物研究所
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