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High-Throughput Assay for Modulators of Mitochondrial Membrane Potential Identifies a Novel Compound With Beneficial Effects on db/db Mice

文献类型：期刊论文

作者Qiu, Bei-Ying1; Turner, Nigel2,3; Li, Yuan-Yuan1; Gu, Min1; Huang, Meng-Wei4; Wu, Fang1; Pang, Tao1; Nan, Fa-Jun1; Ye, Ji-Ming2,5; Li, Jing-Ya1
刊名DIABETES
出版日期2010-01
卷号59期号:1页码:256-265
ISSN号0012-1797
DOI10.2337/db09-0223
文献子类Article
英文摘要OBJECTIVE-Recently, several drugs have been shown to exert beneficial effects for metabolic syndrome through mad regulation of mitochondrial function. Hence, we explored a strategy of targeting mitochondrial function to improve glucose and lipid metabolism. RESEARCH DESIGN AND METHODS-Mitochondrial membrane potential (Delta psi m) is a marker of mitochondrial function; therefore, we set up a high-throughput screening assay of Delta psi m in L6 myotubes. The effects of a selected lead compound were investigated in vitro and in vivo in relation to metabolic syndrome. RESULTS-A novel small-molecule compound, C1, was identified through this high-throughput screening. C1 depolarized Delta psi m in L6 myotubes without cytotoxicity and led to increased cellular AMP-to-ATP ratio, activation of AMP-activated protein kinase (AMPK), and enhanced glucose uptake. It also stimulated the AMPK pathway in HepG2 cells, leading to decreased lipid content. Intriguingly, C1 inhibited respiration in L6 myotubes but did not affect respiration in isolated muscle mitochondria, suggesting that it may depolarize Delta psi m indirectly by affecting the supply of electron donors. Acute administration of C1 in C57BU6J mice markedly increased fat oxidation and the phosphorylation of AMPK and acetyl-CoA carboxylase in the liver. In diabetic db/db mice, chronic administration of Cl significantly reduced hyperglycemia, plasma fatty acids, glucose intolerance, mid the mRNA levels of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase in the liver. CONCLUSIONS-Our results demonstrate a novel small molecule that mildly depolarizes Delta psi m and is able to improve glucose and lipid metabolism to exert beneficial effects for metabolic syndrome. These findings suggest that compounds regulating mitochondrial function may have therapeutic potential for type 2 diabetes. Diabetes 59:256-265, 2010
WOS关键词ACTIVATED PROTEIN-KINASE ; RESPIRATORY COMPLEX-I ; PANCREATIC BETA-CELLS ; PERMEABILITY TRANSITION ; GLUCOSE PHOSPHORYLATION ; HEPATIC GLUCONEOGENESIS ; CELLULAR-ENERGY ; INSULIN ACTION ; METFORMIN ; AMPK
资助项目National Natural Science Foundation of China[U0633008] ; National Natural Science Foundation of China[30472045] ; National Natural Science Foundation of China[30623008] ; Shanghai Commission of Science and Technology[09ZRI407100] ; National Hi-Tech Research and Development Program Grant of China[2007AA09Z402] ; National Hi-Tech Research and Development Program Grant of China[2008AA02Z105] ; National Health and Medical Research Council (NHMRC) of Australia[535930] ; Rebecca Cooper Medical Research Foundation of Australia[00000000] ; China-Australia Special Fund[08400709300] ; NHMRC of Australia[00000000]
WOS研究方向Endocrinology & Metabolism
语种英语
WOS记录号WOS:000273472500033
出版者AMER DIABETES ASSOC
源URL[http://119.78.100.183/handle/2S10ELR8/279016]  
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1.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, State Key Lab Drug Res, Shanghai 200031, Peoples R China;
2.Garvan Inst Med Res, Diabet & Obes Res Program, Sydney, NSW, Australia;
3.Univ New S Wales, St Vincents Hosp, Sch Clin, Sydney, NSW, Australia;
4.Roche R&D Ctr China, Shanghai, Peoples R China;
5.Univ New S Wales, Sch Med Sci, Sydney, NSW, Australia
推荐引用方式
GB/T 7714		 Qiu, Bei-Ying,Turner, Nigel,Li, Yuan-Yuan,et al. High-Throughput Assay for Modulators of Mitochondrial Membrane Potential Identifies a Novel Compound With Beneficial Effects on db/db Mice[J]. DIABETES,2010,59(1):256-265.
APA Qiu, Bei-Ying.,Turner, Nigel.,Li, Yuan-Yuan.,Gu, Min.,Huang, Meng-Wei.,...&Li, Jia.(2010).High-Throughput Assay for Modulators of Mitochondrial Membrane Potential Identifies a Novel Compound With Beneficial Effects on db/db Mice.DIABETES,59(1),256-265.
MLA Qiu, Bei-Ying,et al."High-Throughput Assay for Modulators of Mitochondrial Membrane Potential Identifies a Novel Compound With Beneficial Effects on db/db Mice".DIABETES 59.1(2010):256-265.

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来源：上海药物研究所

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