Selective targeting of nuclear receptor FXR by avermectin analogues with therapeutic effects on nonalcoholic fatty liver disease.
Selective targeting of nuclear receptor FXR by avermectin analogues with therapeutic effects on nonalcoholic fatty liver disease.
复制标题
阿维菌素类似物选择性靶向核受体FXR对非酒精性脂肪肝的治疗作用
DOI：
10.1038/srep17288
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发表时间：
2015-12-01
影响因子：
4.6
通讯作者：
Li Y
中科院分区：
文献类型：
--
作者：
Jin L;Wang R;Zhu Y;Zheng W;Han Y;Guo F;Ye FB;Li Y
非酒精性脂肪性肝病（NAFLD）已成为许多疾病死亡的预测因素。法尼醇X受体（FXR）是NAFLD药物开发的理想靶点，因为它在脂质代谢中起着关键作用。这项工作的目的是研究阿维菌素类似物在调节代谢综合征如NAFLD中调节FXR的分子机制和功能作用。我们发现，在所研究的阿维菌素类似物中，能够结合和激活FXR的类似物在调节所测试的代谢参数方面是有效的，包括以FXR依赖的方式减少肝脏脂质积聚、降低血清胆固醇和葡萄糖水平以及改善胰岛素敏感性。从机理上讲，与FXR相互作用的阿维菌素类似物表现出部分激动剂的特征，在调节辅调节因子募集方面具有独特的特性。还揭示了阿维菌素类似物选择性结合FXR的关键结构特征。这项研究表明，除了抗寄生虫活性，阿维菌素类似物是有希望的候选药物，通过直接靶向FXR治疗代谢综合征，包括NAFLD。此外，通过阿维菌素类似物区分FXR选择性结合的结构特征可以提供一种独特的安全方法来设计靶向FXR信号传导的药物。
Non-alcoholic fatty liver disease (NAFLD) has become a predictive factor of death from many diseases. Farnesoid X receptor (FXR) is an ideal target for NAFLD drug development due to its crucial roles in lipid metabolism. The aim of this work is to examine the molecular mechanisms and functional roles of FXR modulation by avermectin analogues in regulating metabolic syndromes like NAFLD. We found that among avermectin analogues studied, the analogues that can bind and activate FXR are effective in regulating metabolic parameters tested, including reducing hepatic lipid accumulation, lowering serum cholesterol and glucose levels and improving insulin sensitivity, in a FXR dependent manner. Mechanistically, the avermectin analogues that interact with FXR exhibited features as partial agonists, with distinctive properties in modulating coregulator recruitment. Structural features critical for avermectin analogues to selectively bind to FXR were also revealed. This study indicated that in addition to antiparasitic activity, avermectin analogues are promising drug candidates to treat metabolism syndrome including NAFLD by directly targeting FXR. Additionally, the structural features that discriminate the selective binding of FXR by avermectin analogues may provide a unique safe approach to design drugs targeting FXR signaling.