Limits...
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

The therapeutic effects of avermectin analogues to reduce lipid accumulation were dependent on FXR.(a) Oil Red O staining of liver sections (original magnification, ×200). (b) Food intake. (c) Hepatic triglyceride. (d) Serum triglyceride. (e) Serum cholesterol. (f) Serum glucose. WT, Wild type C57BL/6J mice; KO, FXR knockout mice. n = 6 per group, Values are the means ± SEM. *p < 0.05, and ***p < 0.001 versus vehicle.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4664883&req=5

f6: The therapeutic effects of avermectin analogues to reduce lipid accumulation were dependent on FXR.(a) Oil Red O staining of liver sections (original magnification, ×200). (b) Food intake. (c) Hepatic triglyceride. (d) Serum triglyceride. (e) Serum cholesterol. (f) Serum glucose. WT, Wild type C57BL/6J mice; KO, FXR knockout mice. n = 6 per group, Values are the means ± SEM. *p < 0.05, and ***p < 0.001 versus vehicle.

Mentions: To reaffirm that the function of avermectin analogues on lipid metabolism is by directly targeting FXR signaling, we employed wild type mice and FXR gene knockout mice, both fed with high-fat diet, to study the FXR dependency of physiological effects of these avermectin analogues. As shown in Fig. 6a, the liver sections of vehicle control FXR mice showed much larger lipid droplets and more lipid accumulation than those of the vehicle control wild type mice, which was consistent with previous reports14. Compared with the vehicle control wild type mice, treatment with ivermectin, abamectin or doramectin significantly reduced the amount of lipid without affecting food intake (Fig. 6a,b). In contrast, there were nearly no differences observed in FXR mice treated with each of these compounds, demonstrating that FXR was necessary for these compounds to reduce lipid accumulation in mice liver. The data from the chemical kit assay further proved that these compounds exactly significantly decreased the triglyceride levels in wild type mice, but not in FXR mice even though the triglyceride levels were much higher than that in the wild type mice (Fig. 6c). In addition, treatment with all three compounds also decreased the serum triglyceride levels of mice in a FXR dependent manner (Fig. 6d). Similar to ivermectin, doramectin or abamectin treatment also lowered the serum cholesterol and glucose levels in a FXR dependent manner (Fig. 6e,f). The expression pattern of FXR target genes SHP, BSEP, solute carrier family 51 beta subunit (OSTβ) and AKR1B7 in primary hepatocytes from wild type mice and FXR gene knockout mice further confirmed the FXR-dependent manner of avermectin analogues (Supplementary Fig. S5). These results demonstrated that the therapeutic effects of avermectin analogues to regulate metabolism, including lipid, cholesterol and glucose metabolism, are dependent on nuclear receptor FXR.


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)

The therapeutic effects of avermectin analogues to reduce lipid accumulation were dependent on FXR.(a) Oil Red O staining of liver sections (original magnification, ×200). (b) Food intake. (c) Hepatic triglyceride. (d) Serum triglyceride. (e) Serum cholesterol. (f) Serum glucose. WT, Wild type C57BL/6J mice; KO, FXR knockout mice. n = 6 per group, Values are the means ± SEM. *p < 0.05, and ***p < 0.001 versus vehicle.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f6: The therapeutic effects of avermectin analogues to reduce lipid accumulation were dependent on FXR.(a) Oil Red O staining of liver sections (original magnification, ×200). (b) Food intake. (c) Hepatic triglyceride. (d) Serum triglyceride. (e) Serum cholesterol. (f) Serum glucose. WT, Wild type C57BL/6J mice; KO, FXR knockout mice. n = 6 per group, Values are the means ± SEM. *p < 0.05, and ***p < 0.001 versus vehicle.
Mentions: To reaffirm that the function of avermectin analogues on lipid metabolism is by directly targeting FXR signaling, we employed wild type mice and FXR gene knockout mice, both fed with high-fat diet, to study the FXR dependency of physiological effects of these avermectin analogues. As shown in Fig. 6a, the liver sections of vehicle control FXR mice showed much larger lipid droplets and more lipid accumulation than those of the vehicle control wild type mice, which was consistent with previous reports14. Compared with the vehicle control wild type mice, treatment with ivermectin, abamectin or doramectin significantly reduced the amount of lipid without affecting food intake (Fig. 6a,b). In contrast, there were nearly no differences observed in FXR mice treated with each of these compounds, demonstrating that FXR was necessary for these compounds to reduce lipid accumulation in mice liver. The data from the chemical kit assay further proved that these compounds exactly significantly decreased the triglyceride levels in wild type mice, but not in FXR mice even though the triglyceride levels were much higher than that in the wild type mice (Fig. 6c). In addition, treatment with all three compounds also decreased the serum triglyceride levels of mice in a FXR dependent manner (Fig. 6d). Similar to ivermectin, doramectin or abamectin treatment also lowered the serum cholesterol and glucose levels in a FXR dependent manner (Fig. 6e,f). The expression pattern of FXR target genes SHP, BSEP, solute carrier family 51 beta subunit (OSTβ) and AKR1B7 in primary hepatocytes from wild type mice and FXR gene knockout mice further confirmed the FXR-dependent manner of avermectin analogues (Supplementary Fig. S5). These results demonstrated that the therapeutic effects of avermectin analogues to regulate metabolism, including lipid, cholesterol and glucose metabolism, are dependent on nuclear receptor FXR.

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