2-（3-Be nzoylth iou reido）-4,5,6,7-tet ra hydro be n zo [b ] thiophene-3-carboxylic acid ameliorates metabolic disorders in high-fat diet-fed mice  

作　　者：Jin ZHANG Li-na ZHANG Dong-mei CHEN Yan-yun FU Feng ZHANG Ling-ling YANG Chun-mei XIA Hao-wen JIANG Chun-lan TANG Zhi-fu XIE Fan YANG Jia LI Je TANG Jing-ya LI 

机构地区：[1]School of Life Science, East China Normal University, Shanghai 200062, China [2]National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China [3]Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, East China Normal University,Shanghai 200062, China

出　　处：《Acta Pharmacologica Sinica》2015年第4期483-496,共14页中国药理学报（英文版）

基　　金：This work was supported by a grant from 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）, and the National Natural Science Foundation of China （81125023, 81270942, and 81001463）. We thank Tian-cheng DONG for his assistance in the animal experiments.

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 （71001） that inhibited the SREBP-lc 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 ceils was used to discover the compound Two approaches were used to evaluate the lipid-lowering effects of Z J001： （1） diet-induced obesity （DIO） mice that were treated with 71001 （15 mg·kg^-1·d^-1, po） for 7 weeks; and （2） HepG2 ceils and primary hepatocytes used as in vitro models. Results： 71001 （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, 71001 （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.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 （71001） that inhibited the SREBP-lc 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 ceils was used to discover the compound Two approaches were used to evaluate the lipid-lowering effects of Z J001： （1） diet-induced obesity （DIO） mice that were treated with 71001 （15 mg·kg^-1·d^-1, po） for 7 weeks; and （2） HepG2 ceils and primary hepatocytes used as in vitro models. Results： 71001 （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, 71001 （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.

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 

分 类 号：Q959.837[生物学—动物学] TS218[轻工技术与工程—粮食、油脂及植物蛋白工程]