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2-(3-Benzoylthioureido)-4,5,6,7-tetrahydrobenzo[b] thiophene-3-carboxylic acid ameliorates metabolic disorders in high-fat diet-fed mice

文献类型：期刊论文

作者Zhang, Jin1; Zhang, Li-na2; Chen, Dong-mei1; Fu, Yan-yun2; Zhang, Feng3; Yang, Ling-ling1; Xia, Chun-mei2; Jiang, Hao-wen3; Tang, Chun-lan2; Xie, Zhi-fu2
刊名ACTA PHARMACOLOGICA SINICA
出版日期2015-04
卷号36期号:4页码:483-496
关键词2-(3-benzoylthioureido)-4,5,6,7-tetrahydrobenzo[b] thiophene-3-carboxylic acid lipogenesis SREBP-1c AMPK mTOR hepatic lipid accumulation obesity metabolic disorders
ISSN号1671-4083
DOI10.1038/aps.2014.149
文献子类Article
英文摘要Aim: Sterol-regulatory element binding proteins (SREBPs) are major transcription factors that regulate liver lipid biosynthesis. In this article we reported a novel synthetic compound 2-(3-benzoylthioureido)-4,5,6,7-tetrahydrobenzo[b] thiophene-3-carboxylic acid (ZJ001) that inhibited the SREBP-1c pathway, and effectively reduced hepatic lipid accumulation in diet-induced obesity (DIO) mice. Methods: A luciferase reporter driven by an SRE-containing promoter transfected into HepG2 cells was used to discover the compound. Two approaches were used to evaluate the lipid-lowering effects of ZJ001: (1) diet-induced obesity (DIO) mice that were treated with ZJ001 (15 mg.kg(-1).d(-1), po) for 7 weeks; and (2) HepG2 cells and primary hepatocytes used as in vitro models. Results: ZJ001 (10, 20 mu mol/L) dose-dependently inhibited the activity of SRE-containing promoter. ZJ001 administration ameliorated lipid metabolism and improved glucose tolerance in DIO mice, accompanied by significantly reduced mRNA levels of SREBP-1C and SREBP-2, and their downstream genes. In HepG2 cells and insulin-treated hepatocytes, ZJ001 (10-40 mu mol/L) dose-dependently inhibited lipid synthesis, and reduced mRNA levels of SREBP-1C and SREBP-2, and their downstream genes. Furthermore, ZJ001 dose-dependently increased the phosphorylation of AMPK and regulatory-associated protein of mTOR (Raptor), and suppressed the phosphorylation of mTOR in insulin-treated hepatocytes. Moreover, ZJ001 increased the ADP/ATP ratio in insulin-treated hepatocytes, Conclusion: ZJ001 exerts multiple beneficial effects in diet-induced obesity mice. Its lipid-lowering effects may result from the suppression of mTORC1, which regulates SREBP-1c transcription. The results suggest that the SREBP-1c pathway may be a potential therapeutic target for the treatment of lipid metabolic disorders.
WOS关键词ACTIVATED PROTEIN-KINASE ; ELEMENT-BINDING PROTEIN-1C ; INSULIN-RESISTANCE ; LIVER-DISEASE ; TRANSCRIPTION FACTOR ; DIABETES-MELLITUS ; HEPATIC STEATOSIS ; CULTURED-CELLS ; SREBP ACTIVITY ; DIRECT TARGET
资助项目National Program on Key Basic Research Project (973 Program)[2012CB524906] ; National Science and Technology Major Projects for "Major New Drugs Innovation and Development"[2012ZX09301001-004] ; National Natural Science Foundation of China[81125023] ; National Natural Science Foundation of China[81270942] ; National Natural Science Foundation of China[81001463]
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
CSCD记录号CSCD:5392883
WOS记录号WOS:000352203300009
出版者ACTA PHARMACOLOGICA SINICA
源URL[http://119.78.100.183/handle/2S10ELR8/276587]  
专题国家新药筛选中心
中科院受体结构与功能重点实验室
新药研究国家重点实验室
药理学第一研究室
药物安全性评价中心
通讯作者Tang, Jie
作者单位1.E China Normal Univ, Sch Life Sci, Shanghai 200062, Peoples R China;
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China;
3.E China Normal Univ, Shanghai Engn Res Ctr Mol Therapeut & New Drug De, Shanghai 200062, Peoples R China
推荐引用方式
GB/T 7714		 Zhang, Jin,Zhang, Li-na,Chen, Dong-mei,et al. 2-(3-Benzoylthioureido)-4,5,6,7-tetrahydrobenzo[b] thiophene-3-carboxylic acid ameliorates metabolic disorders in high-fat diet-fed mice[J]. ACTA PHARMACOLOGICA SINICA,2015,36(4):483-496.
APA Zhang, Jin.,Zhang, Li-na.,Chen, Dong-mei.,Fu, Yan-yun.,Zhang, Feng.,...&Li, Jing-ya.(2015).2-(3-Benzoylthioureido)-4,5,6,7-tetrahydrobenzo[b] thiophene-3-carboxylic acid ameliorates metabolic disorders in high-fat diet-fed mice.ACTA PHARMACOLOGICA SINICA,36(4),483-496.
MLA Zhang, Jin,et al."2-(3-Benzoylthioureido)-4,5,6,7-tetrahydrobenzo[b] thiophene-3-carboxylic acid ameliorates metabolic disorders in high-fat diet-fed mice".ACTA PHARMACOLOGICA SINICA 36.4(2015):483-496.

入库方式： OAI收割

来源：上海药物研究所

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