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

doi:10.1038/aps.2014.149

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 国家新药筛选中心

	2-(3-Benzoylthioureido)-4,5,6,7-tetrahydrobenzo[b] thiophene-3-carboxylic acid ameliorates metabolic disorders in high-fat diet-fed mice
	Zhang, Jin 1; Zhang, Li-na 2; Chen, Dong-mei 1; Fu, Yan-yun 2; Zhang, Feng 3; Yang, Ling-ling 1; Xia, Chun-mei 2; Jiang, Hao-wen 3; Tang, Chun-lan 2; Xie, Zhi-fu 2
刊名	ACTA PHARMACOLOGICA SINICA
	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
DOI	10.1038/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.
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
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
CSCD记录号	CSCD:5392883
出版者	ACTA PHARMACOLOGICA SINICA
WOS记录号	WOS:000352203300009
内容类型	期刊论文
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.