Celastrol directly binds with VAMP7 and RAB7 to inhibit autophagy and induce apoptosis in preadipocytes
Chenshu Liu1,2, Na Li1,2, Meixiu Peng1,2
1Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.
Abstract:
Obesity is one of the most prevalent chronic metabolic diseases, and induction of apoptosis in preadipocytes and adipocytes is a potential strategy to treat obesity. Celastrol represents one of the most robust anti-obesity phytochemicals so far, yet its direct binding target remains elusive. Here, we determined that celastrol could induce apoptosis in preadipocytes via mitochondrial mediated pathway. Further study clarified that celastrol inhibited the fusion of autophagosome and lysosome to prohibit autophagy, leading to cell apoptosis. By conducting virtual screening and genetic manipulation, we verified that overexpression of VAMP7 and RAB7 could block the effects of celastrol on inhibiting autophagy and inducing apoptosis. The Surface Plasmon Resonance study confirmed the direct binding of celastrol with VAMP7 and RAB7. The functional study illustrated the inhibition of RAB7 GTPase activity after celastrol treatment. Moreover, celastrol induced comparable apoptosis in murine epididymal adipose tissue, human preadipocytes and adipocytes, but not in human hepatocytes. An inhibitory effect on differentiation of human primary visceral preadipocytes was also observed. In conclusion, celastrol exhibited inhibitory effect of autophagy via direct binding with VAMP7 and RAB7, leading to an increase in preadipocytes apoptosis. These results advance our understanding in the potential application of celastrol in treating obesity.
Insights
Celastrol, a potent anti-obesity compound, induces preadipocyte apoptosis by inhibiting autophagy. It directly binds to VAMP7 and RAB7, blocking essential cellular processes and offering a potential obesity treatment.
Area of Science:
- Metabolic Diseases
- Cellular Biology
- Pharmacology
Background:
- Obesity is a prevalent chronic metabolic disease.
- Inducing apoptosis in fat cells is a potential obesity treatment strategy.
- Celastrol is a promising anti-obesity phytochemical with an unknown direct target.
Purpose of the Study:
- To identify the direct binding target of celastrol.
- To elucidate the mechanism by which celastrol exerts its anti-obesity effects.
- To investigate the therapeutic potential of celastrol in obesity.
Main Methods:
- Virtual screening and genetic manipulation to identify celastrol targets.
- Surface Plasmon Resonance (SPR) to confirm direct binding.
- Cell-based assays to study autophagy, apoptosis, and differentiation.
Main Results:
- Celastrol induces apoptosis in preadipocytes via a mitochondrial pathway.
- Celastrol inhibits autophagy by blocking autophagosome-lysosome fusion.
- VAMP7 and RAB7 were identified as direct binding targets, with celastrol inhibiting RAB7 GTPase activity.
- Celastrol induced apoptosis in various fat cells but not hepatocytes, and inhibited preadipocyte differentiation.
Conclusions:
- Celastrol inhibits autophagy through direct binding to VAMP7 and RAB7.
- This leads to increased preadipocyte apoptosis, suggesting celastrol's potential in obesity treatment.
- The findings provide a deeper understanding of celastrol's mechanism of action for metabolic disease therapy.
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