Oleanolic acid derivative NPLC441 potently stimulates glucose transport in 3T3-L1 adipocytes via a multi-target mechanism

doi:10.1016/j.bcp.2008.08.016

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	Oleanolic acid derivative NPLC441 potently stimulates glucose transport in 3T3-L1 adipocytes via a multi-target mechanism
	Lin, Zhonghui; Zhang, Yu; Zhang, Yinan; Shen, Hong; Hu, Lihong; Jiang, Hualiang; Shen, Xu
刊名	BIOCHEMICAL PHARMACOLOGY
	2008-11-15
卷号	76 期号:10 页码:1251-1262
关键词	Oleanolic acid PTP1B LXR alpha:RXR alpha RXR Antagonist 11 beta-HSD1
ISSN号	0006-2952
DOI	10.1016/j.bcp.2008.08.016
文献子类	Article
英文摘要	The natural product oleanolic acid (OA) has been discovered to exhibit varied pharmacological functions including anti-inflammation, anti-tumor and anti-diabetes, while appropriate synthetic oleanolic acid derivatives seem to possess more potent activities. Here we identified a new oleanolic acid derivative, 3-beta-(2-carboxybenzoyloxy)-oleanolic acid (NPLC441), which functioned as a competitive PTP1B inhibitor and enhanced insulin stimulated phosphorylation of IR and AKT in HepG2 cells. As an RXR alpha antagonist, it could selectively activate LXR alpha:RXR alpha heterodimer and increase the promoter activities of ABCA1 and ABCG1 genes in transient transfection assays. Quantitative RT-PCR and Western blot analyses suggested that NPLC441 could up-regulate GLUT4 expression in 3T3-L1 adipocytes, and such effect was further proved to be dependent on LXR alpha:RXR alpha activation. Moreover, 2-deoxyglucose uptake technology-based characterization demonstrated that this compound could stimulate glucose uptake in 3T3-L1 adipocytes. Finally, NPLC441 was observed to be able to suppress 11 beta-HSD1 expression in HepG2 cells, following the discovery that activation of LXRa:RXRa could repress the expression of 11 beta-HSD1. Compared with NPLC441, OA showed no effects on the transactivation of either LXR alpha:RXR alpha heterodimer or RXR alpha-LBD. our work is thus expected to provide a new insight into the anti-diabetic application for oleanolic acid derivatives via multi-target mechanism, and NPLC441 could be used as a potential lead compound for further research. (C) 2008 Elsevier Inc. All rights reserved.
资助项目	State Key Program of Basic Research of China[2004CB518905] ; State Key Program of Basic Research of China[2006AA09Z447] ; State Key Program of Basic Research of China[2007CB914304] ; National Natural Science Foundation of China[30525024] ; National Natural Science Foundation of China[90713046] ; National Natural Science Foundation of China[20721003] ; Shanghai Science and Technology Commission[06JC14080] ; Shanghai Science and Technology Commission[03DZ19228] ; CAS Foundation[KSCX2-YW-R-18]
WOS关键词	LIVER-X-RECEPTOR ; 11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE-1 ; TYROSINE-PHOSPHATASE 1B ; PROLIFERATOR-ACTIVATED RECEPTOR ; RAT ADIPOSE-CELLS ; HUMAN ABCG1 GENE ; INSULIN-RECEPTOR ; URSOLIC ACID ; PTP1B INHIBITOR ; PPAR-GAMMA
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	PERGAMON-ELSEVIER SCIENCE LTD
WOS记录号	WOS:000260950300008
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279432]
专题	上海中药现代化研究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理学第三研究室
通讯作者	Hu, Lihong
作者单位	Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Lin, Zhonghui,Zhang, Yu,Zhang, Yinan,et al. Oleanolic acid derivative NPLC441 potently stimulates glucose transport in 3T3-L1 adipocytes via a multi-target mechanism[J]. BIOCHEMICAL PHARMACOLOGY,2008,76(10):1251-1262.
APA	Lin, Zhonghui.,Zhang, Yu.,Zhang, Yinan.,Shen, Hong.,Hu, Lihong.,...&Shen, Xu.(2008).Oleanolic acid derivative NPLC441 potently stimulates glucose transport in 3T3-L1 adipocytes via a multi-target mechanism.BIOCHEMICAL PHARMACOLOGY,76(10),1251-1262.
MLA	Lin, Zhonghui,et al."Oleanolic acid derivative NPLC441 potently stimulates glucose transport in 3T3-L1 adipocytes via a multi-target mechanism".BIOCHEMICAL PHARMACOLOGY 76.10(2008):1251-1262.