Structure-activity relationship of bile acids and bile acid analogs in regard to FXR activation
Structure-activity relationship of bile acids and bile acid analogs in regard to FXR activation
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DOI：
10.1194/jlr.m300215-jlr200
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发表时间：
2004-01-01
影响因子：
6.5
通讯作者：
Nishimaki-Mogami, T
中科院分区：
文献类型：
--
作者：
Fujino, T;Une, M;Nishimaki-Mogami, T
法尼醇X受体（FXR）是一种胆汁酸激活的核受体，在胆汁酸和胆固醇代谢中起主要作用。为了深入了解FXR配体的结构-活性关系，我们研究了生理配体鹅去氧胆酸[CDCA，（3 α，7 α）]，胆酸[CA;（3 α，7 α，12 α）]、脱氧胆酸[DCA;（3 α，12 α）]和石胆酸（3a）在基于细胞的FXR应答元件驱动的荧光素酶测定和体外共激活因子缔合测定中对FXR活化的影响。将CDCA或CA的羧基转化为醇并没有大大降低它们活化FXR的能力。相比之下，醇的7 β-差向异构体是无活性的，这表明胆汁醇保留了原始胆汁酸的配体性质，并且7 β-羟基削弱了它们的FXR激活作用。类似地，与DCA相比，DCA的羟基差向异构体表现出降低的活性，表明3 β-或12 β-羟基的负面影响。在CDCA的7 β-或3 β-位引入烷基导致FXR活化减少，烷基顺序如下：7-乙基= 7-丙基> 3-甲基> 7-甲基。这些结果表明，无论是羟基还是烷基残基，在类胆甾醇的β-位上的大体积取代基都会降低其激活FXR的能力。
The farnesoid X receptor (FXR) is a bile acid-activated nuclear receptor that plays a major role in bile acid and cholesterol metabolism. To obtain an insight into the structure-activity relationships of FXR ligands, we investigated the functional roles of structural elements in the physiological ligands chenodeoxycholic acid [CDCA, (3alpha,7alpha)], cholic acid [CA; (3alpha,7alpha,12alpha)], deoxycholic acid [DCA; (3alpha,12alpha)], and lithocholic acid (3a) in regard to FXR activation in a cell-based FXR response element-driven luciferase assay and an in vitro coactivator association assay. Conversion of the carboxyl group of CDCA or CA to an alcohol did not greatly diminish their ability to activate FXR. In contrast, the 7beta-epimers of the alcohols were inactive, indicating that the bile alcohols retained the ligand properties of the original bile acids and that the 7beta-hydroxyl group diminished their FXR-activating effect. Similarly, hydroxyl epimers of DCA exhibited decreased activity compared with DCA, indicating a negative effect of 3beta- or 12beta-hydroxyl groups. Introduction of an alkyl group at the 7beta- or 3beta-position of CDCA resulted in diminished FXR activation in the following order of alkyl groups: 7-ethyl = 7-propyl > 3-methyl > 7-methyl. These results indicate that bulky substituents, whether hydroxyl groups or alkyl residues, at the beta-position of cholanoids decrease their ability to activate FXR.