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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 various mice metabolic parameters.(a) Hepatic triglyceride. (b) Body weight. (c) Liver/body weight ratio. (d) Food intake. (e) Serum triglyceride. (f) Serum cholesterol. (g) Relative mRNA levels of genes related with lipid metabolism by real-time PCR. (h) GTT. (i) ITT. n = 6 per group, Values are the means ± SEM. *p < 0.05, **p < 0.01, and ***p < 0.001 versus vehicle.
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f3: Effects of avermectin analogues on various mice metabolic parameters.(a) Hepatic triglyceride. (b) Body weight. (c) Liver/body weight ratio. (d) Food intake. (e) Serum triglyceride. (f) Serum cholesterol. (g) Relative mRNA levels of genes related with lipid metabolism by real-time PCR. (h) GTT. (i) ITT. n = 6 per group, Values are the means ± SEM. *p < 0.05, **p < 0.01, and ***p < 0.001 versus vehicle.

Mentions: The triglyceride levels in liver tissues detected by chemical kit assay also displayed the same results with those liver sections (Fig. 3a). Notably, the body weight and liver/body weight ratio of mice treated with ivermectin, doramectin and abamectin were also significantly lower than those of mice treated with vehicle, eprinomectin and moxidectin (Fig. 3b,c), despite that all compounds had no effect on food intake (Fig. 3d). Since hypertriglyceridemia and hypercholesterolemia are closely related with liver steatosis and atherosclerosis29, we also tested the serum triglyceride and cholesterol levels of mice treated with compounds. The results showed that treatment with ivermectin, doramectin and abamectin significantly decreased the serum triglyceride and cholesterol levels, but treatment with eprinomectin and moxidectin did not (Fig. 3e,f). Obesity can induce elevation of blood glucose, leading to type II diabetes with insulin resistance that may also result in NAFLD by inducing hepatic fat accumulation3031. Impressively, doramectin and abamectin treatment significantly improved glucose tolerance and insulin sensitivity of KK-Ay mice (Fig. 3h,i), which is similar to ivermectin as we reported previously28.


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 various mice metabolic parameters.(a) Hepatic triglyceride. (b) Body weight. (c) Liver/body weight ratio. (d) Food intake. (e) Serum triglyceride. (f) Serum cholesterol. (g) Relative mRNA levels of genes related with lipid metabolism by real-time PCR. (h) GTT. (i) ITT. n = 6 per group, Values are the means ± SEM. *p < 0.05, **p < 0.01, and ***p < 0.001 versus vehicle.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3: Effects of avermectin analogues on various mice metabolic parameters.(a) Hepatic triglyceride. (b) Body weight. (c) Liver/body weight ratio. (d) Food intake. (e) Serum triglyceride. (f) Serum cholesterol. (g) Relative mRNA levels of genes related with lipid metabolism by real-time PCR. (h) GTT. (i) ITT. n = 6 per group, Values are the means ± SEM. *p < 0.05, **p < 0.01, and ***p < 0.001 versus vehicle.
Mentions: The triglyceride levels in liver tissues detected by chemical kit assay also displayed the same results with those liver sections (Fig. 3a). Notably, the body weight and liver/body weight ratio of mice treated with ivermectin, doramectin and abamectin were also significantly lower than those of mice treated with vehicle, eprinomectin and moxidectin (Fig. 3b,c), despite that all compounds had no effect on food intake (Fig. 3d). Since hypertriglyceridemia and hypercholesterolemia are closely related with liver steatosis and atherosclerosis29, we also tested the serum triglyceride and cholesterol levels of mice treated with compounds. The results showed that treatment with ivermectin, doramectin and abamectin significantly decreased the serum triglyceride and cholesterol levels, but treatment with eprinomectin and moxidectin did not (Fig. 3e,f). Obesity can induce elevation of blood glucose, leading to type II diabetes with insulin resistance that may also result in NAFLD by inducing hepatic fat accumulation3031. Impressively, doramectin and abamectin treatment significantly improved glucose tolerance and insulin sensitivity of KK-Ay mice (Fig. 3h,i), which is similar to ivermectin as we reported previously28.

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