5β-Cholane activators of the farnesol X receptor

被引：11
作者：
Fukuchi, J
Song, C
Dai, Q
Hiipakka, RA
Liao, S
机构：
[1] Univ Chicago, Ben May Inst Canc Res, Chicago, IL 60637 USA
[2] Univ Chicago, Dept Biochem & Mol Biol, Chicago, IL 60637 USA
来源：
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY | 2005年 / 94卷 / 04期
关键词：
FXR; bile acids; 5; beta-cholane;
D O I：
10.1016/j.jsbmb.2004.11.012
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
The farnesoid X receptor (FXR) is activated by bile acids, natural agonists for this nuclear receptor. FXR-target genes play important roles in cholesterol and lipid metabolism. We have found that a series of 5 beta-cholanic acid derivatives, even though without a hydroxyl group or any other substituent on the steroidal rings, can activate FXR more potently than hydroxylated bile acids in a reporter gene assay. The most potent compound among these derivatives, N-methyl-5 beta-glycocholanic acid (NMGCA), induces the formation of receptor/coactivator complex in a gel-shift assay and also increases the expression of FXR target genes in human hepatoma HepG2 cells. Furthermore, in rats, NMGCA causes hypolipidemic effects as well as induction of the FXR target genes in liver. Our results suggest that NMGCA and its derivatives are important FXR activators in the study of the physiological functions of FXR and are potentially useful as pharmaceutical agents for treatment of cholesterol and lipid-related diseases. (c) 2004 Elsevier Ltd. All rights reserved.
引用
收藏
页码：311 / 318
页数：8
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