Novel substituted pyrazolone derivatives as AMP-activated protein kinase activators to inhibit lipid synthesis and reduce lipid accumulation in ob/ob mice
文献类型：期刊论文
| 作者 | Zhang, Mei1 ; Xie, Zhi-fu1,2; Zhang, Run-tao1; Chen, Da-kai1; Gu, Min1; Cui, Shi-chao1; Zhang, Yang-ming1; Zhang, Xin-wen1; Yu, Yan-yan1; Li, Jia1
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| 刊名 | ACTA PHARMACOLOGICA SINICA
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| 出版日期 | 2018-10 |
| 卷号 | 39期号:10页码:1622-1632 |
| ISSN号 | 1671-4083 |
| 关键词 | non-alcoholic fatty liver disease AMP-activated protein kinase AMPK activator homogeneous time-resolved fluorescence metabolic disorders ob/ob mice |
| DOI | 10.1038/aps.2017.186 |
| 文献子类 | Article |
| 英文摘要 | Non-alcoholic fatty liver disease (NAFLD) is a clinical syndrome characterized by hepatic steatosis. NAFLD is closely linked to obesity, insulin resistance and dyslipidemia. AMP-activated protein kinase (AMPK) functions as an energy sensor and plays a central role in regulating lipid metabolism. In this study, we identified a series of novel pyrazolone AMPK activators using a homogeneous timeresolved fluorescence assay (HTRF) based on the AMPK alpha 2 beta 1 gamma 1 complex. Compound 29 (C29) is a candidate compound that directly activated the kinase domain of AMPK with an EC50 value of 2.1-0.2 mu mol/L and acted as a non-selective activator of AMPK complexes. Treatment of HepG2 cells with C29 (20, 40 mu mol/L) dose-dependently inhibited triglyceride accumulation. Chronic administration of C29 (10, 30 mg/kg every day, po, for 5 weeks) significantly improved lipid metabolism in both the liver and the plasma of ob/ob mice. These results demonstrate that the AMPK activators could be part of a novel treatment approach for NAFLD and associated metabolic disorders. |
| WOS关键词 | FATTY LIVER-DISEASE ; INSULIN-RESISTANCE ; HEPATIC STEATOSIS ; SKELETAL-MUSCLE ; PHOSPHORYLATION ; HOMEOSTASIS ; LIPOGENESIS ; HYPERTROPHY ; MECHANISMS ; EXPRESSION |
| 资助项目 | National Natural Science Foundation of China[81502910] ; National Natural Science Foundation of China[81273566] ; National Natural Science Foundation of China[81673489] ; Shanghai Commission of Science and Technology[15ZR1447900] ; Shanghai Commission of Science and Technology[14431902800] ; Youth Innovation Association of Chinese Academy of Sciences[00000000] ; National Key Research and Development Program of China[2016YFC1305500] |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| 出版者 | ACTA PHARMACOLOGICA SINICA |
| WOS记录号 | WOS:000448391500008 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/279555]  |
| 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 |
| 通讯作者 | Nan, Fa-jun; Li, Jing-ya |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Drug Screening Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhang, Mei,Xie, Zhi-fu,Zhang, Run-tao,et al. Novel substituted pyrazolone derivatives as AMP-activated protein kinase activators to inhibit lipid synthesis and reduce lipid accumulation in ob/ob mice[J]. ACTA PHARMACOLOGICA SINICA,2018,39(10):1622-1632. |
| APA | Zhang, Mei.,Xie, Zhi-fu.,Zhang, Run-tao.,Chen, Da-kai.,Gu, Min.,...&Li, Jing-ya.(2018).Novel substituted pyrazolone derivatives as AMP-activated protein kinase activators to inhibit lipid synthesis and reduce lipid accumulation in ob/ob mice.ACTA PHARMACOLOGICA SINICA,39(10),1622-1632. |
| MLA | Zhang, Mei,et al."Novel substituted pyrazolone derivatives as AMP-activated protein kinase activators to inhibit lipid synthesis and reduce lipid accumulation in ob/ob mice".ACTA PHARMACOLOGICA SINICA 39.10(2018):1622-1632. |
入库方式： OAI收割
来源：上海药物研究所
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