@article{APS9414,
author = {Jin ZHANG and Li-na ZHANG and Dong-mei CHEN and Yan-yun FU and Feng ZHANG and Ling-ling YANG and Chun-mei XIA and Hao-wen JIANG and Chun-lan TANG and Zhi-fu XIE and Fan YANG and Jia LI and Jie TANG and Jing-ya LI},
title = {2-(3-Benzoylthioureido)-4,5,6,7-tetrahydrobenzo[b] thiophene-3-carboxylic acid ameliorates metabolic disorders in high-fat diet-fed mice},
journal = {Acta Pharmacologica Sinica},
volume = {36},
number = {4},
year = {2017},
keywords = {},
abstract = {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 μmol/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 μmol/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.},
issn = {1745-7254}, url = {http://www.chinaphar.com/article/view/9414}
}