title: Selective targeting of nuclear receptor FXR by avermectin analogues with therapeutic effects on nonalcoholic fatty liver disease.
abstract: 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.
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian 361005, China.|State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian 361005, China.
authors.forename: Lihua
authors.initials: L
authors.lastname: Jin
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian 361005, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian 361005, China.
authors.forename: Yanlin
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian 361005, China.
authors.forename: Weili
authors.initials: W
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian 361005, China.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Han
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian 361005, China.
authors.forename: Fusheng
authors.initials: F
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian 361005, China.
authors.forename: Frank Bin
authors.initials: FB
authors.lastname: Ye
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian 361005, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D016503:Drug Delivery Systems / Q000379:methods*; D004353:Drug Evaluation, Preclinical; D007559:Ivermectin / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D007559:Ivermectin; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C019264:avermectin