Deciphering the nuclear bile acid receptor FXR paradigm.
Deciphering the nuclear bile acid receptor FXR paradigm.
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DOI：
10.1621/nrs.08005
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发表时间：
2010-11-19
期刊：
影响因子：
--
通讯作者：
Moschetta A
中科院分区：
文献类型：
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作者：
Modica S;Gadaleta RM;Moschetta A
最初被称为维甲酸X受体相互作用蛋白14(RIP14)的法尼醇X受体(FXR)，因其能够结合超生理浓度的法尼醇而被重新命名。1999年，由于初级胆汁酸被确定为天然配体，FXR被去孤儿。FXR在肝脏和肠道中强烈表达，已被证明是几种肠道-肝脏代谢途径的主要转录调节因子，与胆汁淤积、脂肪肝、胆固醇结石疾病、肠道炎症和肿瘤等疾病的病理生理相关。此外，鉴于FXR在肠道-肝轴反馈调节脂肪和葡萄糖动态平衡中的重要性，FXR的调节似乎在代谢综合征和糖尿病等疾病中有很大的作用。几个细胞和动物模型的令人兴奋的结果为合成FXR配体作为新的药理制剂提供了动力。FXR发现14年来，已经从长凳走到了床边；一种新的核受体配体正在进入临床应用。
Originally called retinoid X receptor interacting protein 14 (RIP14), the farnesoid X receptor (FXR) was renamed after the ability of its rat form to bind supra-physiological concentrations of farnesol. In 1999 FXR was de-orphanized since primary bile acids were identified as natural ligands. Strongly expressed in the liver and intestine, FXR has been shown to be the master transcriptional regulator of several entero-hepatic metabolic pathways with relevance to the pathophysiology of conditions such as cholestasis, fatty liver disease, cholesterol gallstone disease, intestinal inflammation and tumors. Furthermore, given the importance of FXR in the gut-liver axis feedbacks regulating lipid and glucose homeostasis, FXR modulation appears to have great input in diseases such as metabolic syndrome and diabetes. Exciting results from several cellular and animal models have provided the impetus to develop synthetic FXR ligands as novel pharmacological agents. Fourteen years from its discovery, FXR has gone from bench to bedside; a novel nuclear receptor ligand is going into clinical use.