Novel Small-Molecule AMP-Activated Protein Kinase Allosteric Activator with Beneficial Effects in db/db Mice
文献类型：期刊论文
| 作者 | Zhang, Li-Na; Xu, Lei; Zhou, Hua-Yong; Wu, Ling-Yan; Li, Yuan-Yuan; Pang, Tao; Xia, Chun-Mei; Qiu, Bei-Ying; Gu, Min ; Dong, Tian-Cheng
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| 刊名 | PLOS ONE
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| 出版日期 | 2013-08-20 |
| 卷号 | 8期号:8 |
| ISSN号 | 1932-6203 |
| DOI | 10.1371/journal.pone.0072092 |
| 文献子类 | Article |
| 英文摘要 | AMP-activated protein kinase (AMPK) is an energy sensor of metabolism that is an attractive therapeutic target for type 2 diabetes mellitus and metabolic syndrome. Using a homogeneous scintillation proximity assay (SPA), we identified a new small-molecule AMPK activator, ZLN024, which allosterically stimulated active AMPK heterotrimers and the inactive alpha 1 subunit truncations alpha 1 (1-394) and alpha 1 (1-335) but not alpha 1 (1-312). AMPK activation by ZLN024 requires the pre-phosphorylation of Thr-172 by at least one upstream kinase and protects AMPK Thr-172 against dephosphorylation by PP2C alpha. ZLN024 activated AMPK in L6 myotubes and stimulated glucose uptake and fatty acid oxidation without increasing the ADP/ATP ratio. ZLN024 also activated AMPK in primary hepatocytes, decreased fatty acid synthesis and glucose output. Treatment of db/db mice with 15 mg/kg/day ZLN024 improved glucose tolerance; liver tissue weight, triacylglycerol and the total cholesterol content were decreased. The hepatic transcriptional level of G6Pase, FAS and mtGPAT were reduced. The transcription of genes involved in fatty acid oxidation and the mitochondrial biogenesis of muscle tissue were elevated. The ACC phosphorylation was increased in muscle and liver. This study provides a novel allosteric AMPK activator for functional study in vitro and in vivo and demonstrates that AMPK allosteric activators could be a promising therapeutic approach for type 2 diabetes mellitus and metabolic syndrome. |
| WOS关键词 | SCINTILLATION PROXIMITY ASSAY ; MOUSE SKELETAL-MUSCLE ; RESPIRATORY COMPLEX-I ; 5-AMINOIMIDAZOLE-4-CARBOXAMIDE RIBONUCLEOSIDE ; METABOLIC SYNDROME ; INSULIN ACTION ; DRUG TARGET ; RAT-LIVER ; MECHANISM ; METFORMIN |
| 资助项目 | National Natural Science Foundation of China[81125023] ; National Natural Science Foundation of China[81273566] ; National Science and Technology Major Projects for Major New Drugs Innovation and Development[2012ZX09304011] ; National Science and Technology Major Projects for Major New Drugs Innovation and Development[2012ZX09301-001-004] ; National Program on Key Basic Research Project[2012CB524906] ; National Program on Key Basic Research Project[G1998051104] ; Shanghai Commission of Science and Technology[11DZ2292200] |
| WOS研究方向 | Science & Technology - Other Topics |
| 语种 | 英语 |
| WOS记录号 | WOS:000324527300062 |
| 出版者 | PUBLIC LIBRARY SCIENCE |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277501]  |
| 专题 | 国家新药筛选中心 药物化学研究室 药理学第一研究室 药物安全性评价中心 |
| 通讯作者 | Li, Jia |
| 作者单位 | Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai 200031, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhang, Li-Na,Xu, Lei,Zhou, Hua-Yong,et al. Novel Small-Molecule AMP-Activated Protein Kinase Allosteric Activator with Beneficial Effects in db/db Mice[J]. PLOS ONE,2013,8(8). |
| APA | Zhang, Li-Na.,Xu, Lei.,Zhou, Hua-Yong.,Wu, Ling-Yan.,Li, Yuan-Yuan.,...&Li, Jia.(2013).Novel Small-Molecule AMP-Activated Protein Kinase Allosteric Activator with Beneficial Effects in db/db Mice.PLOS ONE,8(8). |
| MLA | Zhang, Li-Na,et al."Novel Small-Molecule AMP-Activated Protein Kinase Allosteric Activator with Beneficial Effects in db/db Mice".PLOS ONE 8.8(2013). |
入库方式： OAI收割
来源：上海药物研究所
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