Identification of 15d-PGJ(2) as an antagonist of farnesoid X receptor: Molecular modeling with biological evaluation

doi:10.1016/j.steroids.2013.04.018

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	Identification of 15d-PGJ(2) as an antagonist of farnesoid X receptor: Molecular modeling with biological evaluation
	Xu, Xing; Lul, Yin; Chen, Lili; Chen, Jing; Luo, Xiaomin; Shen, Xu
刊名	STEROIDS
	2013-09
卷号	78 期号:9 页码:813-822
关键词	15-Deoxy-Delta(12,14)PGJ(2) Farnesoid X receptor Antagonist Molecular dynamics simulation
ISSN号	0039-128X
DOI	10.1016/j.steroids.2013.04.018
文献子类	Article
英文摘要	15-Deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)) is one of the major metabolites from prostaglandin D-2 in arachidonic acid (AA) metabolic pathway. It was determined as a ligand of peroxisome proliferator-activated receptor gamma (PPAR gamma) functioning potently in adipocyte development. However, the fact that 15d-PGJ(2) exerts also PPAR gamma-independent biological actions has highly addressed its multi-target behavior. Here, we identified that 15d-PGJ(2) was an antagonist of farnesoid X receptor (FXR), as investigated by surface plasmon resonance, fluorescence quenching and homo time-resolved fluorescence based analyses, and the coactivator-recruitment and luciferase-reporter related investigation. Assay of 15d-PGJ(2) regulation on hFXR alpha target genes revealed that treatment of HepG2 cells with 15d-PGJ(2) resulted in the stimulation of mRNA expressions of bile-salt export pump (BSEP), and the decrease of cholesterol 7a-hydroxylase (CYP7a1). In addition, functional assays indicated that 15d-PGJ(2) promoted the conversion of cholesterol to bile acids in HepG2 cells. Moreover, molecular docking combined with molecular dynamics simulation was applied to develop the possible model of 15d-PGJ(2) binding to hFXR alpha ligand binding domain (LBD) at atomic level, and the responsible residues for 15d-PGJ(2)/hFXR alpha-LBD interaction were thereby determined, which were further confirmed by SPR assays against hFXR alpha-LBD site-directed mutations. Given that hFXR alpha functions potently in the regulation of hepatic bile acid metabolism and lipid/glucose homeostasis, our current work is expected to help better understand the multi-target features of this PGD(2) metabolite in biological pathways, and 15d-PGJ(2) as a new discovered FXR antagonist might find its potential application in further anti-hypercholesterol research. (C) 2013 Elsevier Inc. All rights reserved.
资助项目	State Key Program of Basic Research of China[2010CB912501] ; National Natural Science Foundation of China[81220108025] ; National Natural Science Foundation of China[81173105] ; National Natural Science Foundation of China[91213306] ; Science Foundation of Shanghai[11XD1406100] ; Foundation of Chinese Academy of Sciences[KSCX2-EW-Q-3] ; Basic Research Project of Shanghai Science and Technology Commission[09ZR1438000]
WOS关键词	BILE-ACID RECEPTOR ; PROMOTES ADIPOCYTE DIFFERENTIATION ; PARTICLE MESH EWALD ; DRUG-LIKE MOLECULES ; SALT EXPORT PUMP ; PPAR-GAMMA ; NUCLEAR-RECEPTOR ; 15-DEOXY-DELTA(12,14)-PROSTAGLANDIN J(2) ; SIGNALING PATHWAY ; ACCURATE DOCKING
WOS研究方向	Biochemistry & Molecular Biology ; Endocrinology & Metabolism
语种	英语
出版者	ELSEVIER SCIENCE INC
WOS记录号	WOS:000322934700004
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277493]
专题	生物技术药物研发中心（筹）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发现与设计中心药理学第三研究室
通讯作者	Chen, Lili
作者单位	Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Xu, Xing,Lul, Yin,Chen, Lili,et al. Identification of 15d-PGJ(2) as an antagonist of farnesoid X receptor: Molecular modeling with biological evaluation[J]. STEROIDS,2013,78(9):813-822.
APA	Xu, Xing,Lul, Yin,Chen, Lili,Chen, Jing,Luo, Xiaomin,&Shen, Xu.(2013).Identification of 15d-PGJ(2) as an antagonist of farnesoid X receptor: Molecular modeling with biological evaluation.STEROIDS,78(9),813-822.
MLA	Xu, Xing,et al."Identification of 15d-PGJ(2) as an antagonist of farnesoid X receptor: Molecular modeling with biological evaluation".STEROIDS 78.9(2013):813-822.