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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

Effects of avermectin analogues on liver fat.(a) The liver morphology of mice. (b) H&E staining of liver sections (original magnification, ×200). (c) Oil Red O staining of liver sections (original magnification, ×200).
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f2: Effects of avermectin analogues on liver fat.(a) The liver morphology of mice. (b) H&E staining of liver sections (original magnification, ×200). (c) Oil Red O staining of liver sections (original magnification, ×200).

Mentions: In our previous study, we found that the antiparasitic drug ivermectin can target mammalian FXR to regulate cholesterol and glucose metabolism, which make us wonder whether this unique antiparasitic FXR ligand has therapeutic effects on NAFLD by regulating lipid metabolism, and whether other macrocyclic lactone analogues have similar effects on metabolism. Ivermectin together with abamectin, doramectin, eprinomectin and moxidectin selected from avermectins and milbemycins, respectively (Fig. 1), were used to investigate the physiological effects in diabetic mice. 10-week age male KK-Ay mice were fed with high-fat diet and intraperitoneally (i.p.) injected once daily with vehicle, GW4064 and compounds mentioned above. After compound treatment for 14 days, the liver from mice treated with various compounds displayed obvious differences in both morphology and pathology. Remarkably, the livers of mice treated with ivermectin, doramectin and abamectin showed much more fresh red tissue (Fig. 2a). In contrast, the liver color of mice treated with vehicle, eprinomectin and moxidectin was grease white, whereas the livers of mice treated with GW4064 showed a little fresh red. We then performed haematoxylin and eosin (H&E) staining of the paraffin-embedded liver sections, which revealed similar results and explained the observations above (Fig. 2b). Histological examination of liver sections obtained from vehicle treated KK-Ay mice showed the extensive existence of vesicular hepatocyte vacuolation, while GW4064 slightly reduced the hepatic lipid. However, ivermectin, doramectin and abamectin treatment nearly completely reverse the liver from hepatic steatosis in the diabetic mice with the disappeared hepatic lipid accumulation and tight compact structure of the liver cells. In contrast, hepatocellular vacuolation was similar or worse in liver treated with moxidectin and eprinomectin compared with vehicle control. To further confirm the lipid accumulation, we performed oil red O staining of the frozen liver sections (Fig. 2c). As expected, liver sections from vehicle treated mice showed abundant lipid accumulation, especially containing many large lipid droplets. GW4064 treatment slightly reduced the lipid accumulation, while liver sections from mice treated with ivermectin, abamectin and doramectin dramatically reduced the lipid accumulation, where the large lipid droplets nearly disappeared. In contrast, the lipid accumulation was similar with the vehicle control in liver sections of mice treated with moxidectin and eprinomectin.


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)

Effects of avermectin analogues on liver fat.(a) The liver morphology of mice. (b) H&E staining of liver sections (original magnification, ×200). (c) Oil Red O staining of liver sections (original magnification, ×200).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2: Effects of avermectin analogues on liver fat.(a) The liver morphology of mice. (b) H&E staining of liver sections (original magnification, ×200). (c) Oil Red O staining of liver sections (original magnification, ×200).
Mentions: In our previous study, we found that the antiparasitic drug ivermectin can target mammalian FXR to regulate cholesterol and glucose metabolism, which make us wonder whether this unique antiparasitic FXR ligand has therapeutic effects on NAFLD by regulating lipid metabolism, and whether other macrocyclic lactone analogues have similar effects on metabolism. Ivermectin together with abamectin, doramectin, eprinomectin and moxidectin selected from avermectins and milbemycins, respectively (Fig. 1), were used to investigate the physiological effects in diabetic mice. 10-week age male KK-Ay mice were fed with high-fat diet and intraperitoneally (i.p.) injected once daily with vehicle, GW4064 and compounds mentioned above. After compound treatment for 14 days, the liver from mice treated with various compounds displayed obvious differences in both morphology and pathology. Remarkably, the livers of mice treated with ivermectin, doramectin and abamectin showed much more fresh red tissue (Fig. 2a). In contrast, the liver color of mice treated with vehicle, eprinomectin and moxidectin was grease white, whereas the livers of mice treated with GW4064 showed a little fresh red. We then performed haematoxylin and eosin (H&E) staining of the paraffin-embedded liver sections, which revealed similar results and explained the observations above (Fig. 2b). Histological examination of liver sections obtained from vehicle treated KK-Ay mice showed the extensive existence of vesicular hepatocyte vacuolation, while GW4064 slightly reduced the hepatic lipid. However, ivermectin, doramectin and abamectin treatment nearly completely reverse the liver from hepatic steatosis in the diabetic mice with the disappeared hepatic lipid accumulation and tight compact structure of the liver cells. In contrast, hepatocellular vacuolation was similar or worse in liver treated with moxidectin and eprinomectin compared with vehicle control. To further confirm the lipid accumulation, we performed oil red O staining of the frozen liver sections (Fig. 2c). As expected, liver sections from vehicle treated mice showed abundant lipid accumulation, especially containing many large lipid droplets. GW4064 treatment slightly reduced the lipid accumulation, while liver sections from mice treated with ivermectin, abamectin and doramectin dramatically reduced the lipid accumulation, where the large lipid droplets nearly disappeared. In contrast, the lipid accumulation was similar with the vehicle control in liver sections of mice treated with moxidectin and eprinomectin.

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