The antiparasitic drug ivermectin is a novel FXR ligand that regulates metabolism

Lihua Jin, Xuhui Feng, Hui Rong, Zhifu Pan, Yuka Inaba, Lin Qiu, Weili Zheng, Shengchen Lin, Rui Wang, Zhao Wang, Shanshan Wang, Hongyan Liu, Song Li, Wen Xie and Yong Li ()
Additional contact information
Lihua Jin: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University
Xuhui Feng: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University
Hui Rong: Center for Pharmacogenetics, University of Pittsburgh
Zhifu Pan: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University
Yuka Inaba: Center for Pharmacogenetics, University of Pittsburgh
Lin Qiu: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University
Weili Zheng: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University
Shengchen Lin: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University
Rui Wang: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University
Zhao Wang: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University
Shanshan Wang: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University
Hongyan Liu: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University
Song Li: Center for Pharmacogenetics, University of Pittsburgh
Wen Xie: Center for Pharmacogenetics, University of Pittsburgh
Yong Li: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University

Nature Communications, 2013, vol. 4, issue 1, 1-8

Abstract: Abstract Farnesoid X receptor (FXR) has important roles in maintaining bile acid and cholesterol homeostasis. Here we report that the antiparasitic drug ivermectin is a ligand for nuclear FXR. We identify ivermectin using a high-throughput compound library screening and show that it induces the transcriptional activity of the FXR with distinctive properties in modulating coregulator recruitment. The crystal structure of ivermectin complexed with the ligand-binding domain of FXR reveals a unique binding mode of ivermectin in the FXR ligand-binding pocket, including the highly dynamic AF-2 helix and an expanded ligand-binding pocket. Treatment of wild-type mice, but not of FXR-null mice, with ivermectin decreases serum glucose and cholesterol levels, suggesting that ivermectin regulates metabolism through FXR. Our results establish FXR as the first mammalian protein targeted by ivermectin with high selectivity. Considering that ivermectin is a widely used clinical drug, our findings reveal a safe template for the design of novel FXR ligands.

Date: 2013
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DOI: 10.1038/ncomms2924

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