The antiparasitic drug ivermectin is a novel FXRligand that regulates metabolism

摘要

Farnesoid X receptor (FXR) has important roles in maintaining bile acid and cholesterolhomeostasis. 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 itinduces the transcriptional activity of the FXR with distinctive properties in modulating coregulatorrecruitment. The crystal structure of ivermectin complexed with the ligand-bindingdomain 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 ofwild-type mice, but not of FXR-null mice, with ivermectin decreases serum glucose andcholesterol levels, suggesting that ivermectin regulates metabolism through FXR. Our resultsestablish 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 templatefor the design of novel FXR ligands.