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Selective targeting of nuclear receptor FXR by avermectin analogues with therapeutic effects on nonalcoholic fatty liver disease.

Jin L, Wang R, Zhu Y, Zheng W, Han Y, Guo F, Ye FB, Li Y - Sci Rep (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian 361005, China.

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.

No MeSH data available.


Related in: MedlinePlus

Relative binding affinity of various peptide motifs to the FXR LBD in the presence of avermectin analogues as determined by peptide competition assays.Various unlabeled peptides (20 μM) are used to compete off the binding of the biotin-labeled SRC2-3 LXXLL motif to FXR LBD in response to 1 μM ivermectin, abamectin, doramectin, or 0.5 μM GW4064, respectively. Values are the means ± SEM of three independent experiments. Sequences of peptides used in the AlphaScreen assays are as described previously28.
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f5: Relative binding affinity of various peptide motifs to the FXR LBD in the presence of avermectin analogues as determined by peptide competition assays.Various unlabeled peptides (20 μM) are used to compete off the binding of the biotin-labeled SRC2-3 LXXLL motif to FXR LBD in response to 1 μM ivermectin, abamectin, doramectin, or 0.5 μM GW4064, respectively. Values are the means ± SEM of three independent experiments. Sequences of peptides used in the AlphaScreen assays are as described previously28.

Mentions: Peptide profiling is a powerful tool to detect ligand-dependent conformational properties of nuclear receptor LBDs and the correlations receptor binding with functions of nuclear receptor ligands4041. For example, peptide profiling is particularly useful to discern the conformational differences of estrogen receptor (ER) in response to binding of agonists, antagonists and SERMs (selective ER modulators)41. To determine whether there is a conformational difference of FXR with various avermectin analogues, we performed peptide-profiling experiments using a panel of 16 unlabelled peptides selected from both coactivators and corepressors to compete off the binding of the third LXXLL motif of SRC2 (SRC2–3) to FXR in response to the binding of avermectin analogues (Fig. 5). The result revealed that the doramectin or abamectin bound FXR has identical peptide profiles as the ivermectin (Fig. 5), suggesting that FXR bound with these three avermectin analogues essentially adopts identical conformations. Consistent with the results above, corepressor motifs, including silencing mediator of retinoid and thyroid receptors (SMRT)-2, substantially inhibited the SRC2 binding to FXR in response to avermectin analogues, but not GW4064-bound FXR. Our results suggest a partial agonist nature of avermectin analogues with unique properties in modulating coregulator recruitment.


Selective targeting of nuclear receptor FXR by avermectin analogues with therapeutic effects on nonalcoholic fatty liver disease.

Jin L, Wang R, Zhu Y, Zheng W, Han Y, Guo F, Ye FB, Li Y - Sci Rep (2015)

Relative binding affinity of various peptide motifs to the FXR LBD in the presence of avermectin analogues as determined by peptide competition assays.Various unlabeled peptides (20 μM) are used to compete off the binding of the biotin-labeled SRC2-3 LXXLL motif to FXR LBD in response to 1 μM ivermectin, abamectin, doramectin, or 0.5 μM GW4064, respectively. Values are the means ± SEM of three independent experiments. Sequences of peptides used in the AlphaScreen assays are as described previously28.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4664883&req=5

f5: Relative binding affinity of various peptide motifs to the FXR LBD in the presence of avermectin analogues as determined by peptide competition assays.Various unlabeled peptides (20 μM) are used to compete off the binding of the biotin-labeled SRC2-3 LXXLL motif to FXR LBD in response to 1 μM ivermectin, abamectin, doramectin, or 0.5 μM GW4064, respectively. Values are the means ± SEM of three independent experiments. Sequences of peptides used in the AlphaScreen assays are as described previously28.
Mentions: Peptide profiling is a powerful tool to detect ligand-dependent conformational properties of nuclear receptor LBDs and the correlations receptor binding with functions of nuclear receptor ligands4041. For example, peptide profiling is particularly useful to discern the conformational differences of estrogen receptor (ER) in response to binding of agonists, antagonists and SERMs (selective ER modulators)41. To determine whether there is a conformational difference of FXR with various avermectin analogues, we performed peptide-profiling experiments using a panel of 16 unlabelled peptides selected from both coactivators and corepressors to compete off the binding of the third LXXLL motif of SRC2 (SRC2–3) to FXR in response to the binding of avermectin analogues (Fig. 5). The result revealed that the doramectin or abamectin bound FXR has identical peptide profiles as the ivermectin (Fig. 5), suggesting that FXR bound with these three avermectin analogues essentially adopts identical conformations. Consistent with the results above, corepressor motifs, including silencing mediator of retinoid and thyroid receptors (SMRT)-2, substantially inhibited the SRC2 binding to FXR in response to avermectin analogues, but not GW4064-bound FXR. Our results suggest a partial agonist nature of avermectin analogues with unique properties in modulating coregulator recruitment.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian 361005, China.

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.

No MeSH data available.


Related in: MedlinePlus