Novel small-molecule AMPK activator orally exerts beneficial effects on diabetic db/db mice

doi:10.1016/j.taap.2013.09.006

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	Novel small-molecule AMPK activator orally exerts beneficial effects on diabetic db/db mice
	Li, Yuan-Yuan; Yu, Li-Fang; Zhang, Li-Na; Qiu, Bei-Ying; Su, Ming-Bo; Wu, Fang; Chen, Da-Kai; Pang, Tao; Gu, Min; Zhang, Wei
刊名	TOXICOLOGY AND APPLIED PHARMACOLOGY
	2013-12-01
卷号	273 期号:2 页码:325-334
关键词	AMPK Activator Allosteric Small-molecule Orally effective Metabolic syndrome
ISSN号	0041-008X
DOI	10.1016/j.taap.2013.09.006
文献子类	Article
英文摘要	AMP-activated protein kinase (AMPK), which is a pivotal guardian of whole-body energy metabolism, has become an attractive therapeutic target for metabolic syndrome. Previously, using a homogeneous scintillation proximity assay, we identified the small-molecule AMPK activator C24 from an optimization based on the original allosteric activator PT1. In this paper, the AMPK activation mechanism of C24 and its potential beneficial effects on glucose and lipid metabolism on db/db mice were investigated. C24 allosterically stimulated inactive AMPK alpha subunit truncations and activated AMPK heterotrimers by antagonizing autoinhibition. In primary hepatocytes, C24 increased the phosphorylation of AMPK downstream target acetyl-CoA carboxylase dose-dependently without changing intracellular AMP/ATP ratio, indicating its allosteric activation in cells. Through activating AMPK, C24 decreased glucose output by down-regulating mRNA levels of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) in primary hepatocytes. C24 also decreased the triglyceride and cholesterol contents in HepG2 cells. Due to its improved bioavailability, chronic oral treatment with multiple doses of 04 significantly reduced blood glucose and lipid levels in plasma, and improved the glucose tolerance of diabetic db/db mice. The hepatic transcriptional levels of PEPCK and G6Pase were reduced. These results demonstrate that this orally effective activator of AMPK represents a novel approach to the treatment of metabolic syndrome. (C) 2013 Elsevier Inc. All rights reserved.
资助项目	National Natural Science Foundation of China[81125023] ; National Natural Science Foundation of China[81273566] ; National Program on Key Basic Research Project[2012CB524906] ; 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 Science and Technology Major Projects for Major New Drugs Innovation and Development[2013ZX09507002] ; Shanghai Commission of Science and Technology[11DZ2292200]
WOS关键词	PROTEIN-KINASE ; SKELETAL-MUSCLE ; MECHANISM ; METFORMIN ; METABOLISM ; LEPTIN ; ENERGY ; LIVER ; AICAR ; IDENTIFICATION
WOS研究方向	Pharmacology & Pharmacy ; Toxicology
语种	英语
出版者	ACADEMIC PRESS INC ELSEVIER SCIENCE
WOS记录号	WOS:000328099500009
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277358]
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, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Li, Yuan-Yuan,Yu, Li-Fang,Zhang, Li-Na,et al. Novel small-molecule AMPK activator orally exerts beneficial effects on diabetic db/db mice[J]. TOXICOLOGY AND APPLIED PHARMACOLOGY,2013,273(2):325-334.
APA	Li, Yuan-Yuan.,Yu, Li-Fang.,Zhang, Li-Na.,Qiu, Bei-Ying.,Su, Ming-Bo.,...&Li, Jia.(2013).Novel small-molecule AMPK activator orally exerts beneficial effects on diabetic db/db mice.TOXICOLOGY AND APPLIED PHARMACOLOGY,273(2),325-334.
MLA	Li, Yuan-Yuan,et al."Novel small-molecule AMPK activator orally exerts beneficial effects on diabetic db/db mice".TOXICOLOGY AND APPLIED PHARMACOLOGY 273.2(2013):325-334.