Novel Small-Molecule AMP-Activated Protein Kinase Allosteric Activator with Beneficial Effects in db/db Mice

doi:10.1371/journal.pone.0072092

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	Novel Small-Molecule AMP-Activated Protein Kinase Allosteric Activator with Beneficial Effects in db/db Mice
	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
刊名	PLOS ONE
	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.
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
WOS研究方向	Science & Technology - Other Topics
语种	英语
出版者	PUBLIC LIBRARY SCIENCE
WOS记录号	WOS:000324527300062
内容类型	期刊论文
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).