Liu Chenshu, Li Na, Peng Meixiu, Huang Kan, Fan Dongxiao, Zhao Zhengde, Huang Xiuyi, Liu Yunchong, Chen Sifan, Li Zilun
Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.
National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.
Front Pharmacol. 2023 Mar 7;14:1094584. doi: 10.3389/fphar.2023.1094584. eCollection 2023.
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 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 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.
肥胖是最常见的慢性代谢性疾病之一，诱导前脂肪细胞和脂肪细胞凋亡是治疗肥胖的一种潜在策略。雷公藤红素是迄今为止最有效的抗肥胖植物化学物质之一，但其直接结合靶点仍不清楚。在这里，我们确定雷公藤红素可通过线粒体介导的途径诱导前脂肪细胞凋亡。进一步的研究表明，雷公藤红素抑制自噬体与溶酶体的融合以阻止自噬，从而导致细胞凋亡。通过虚拟筛选和基因操作，我们证实VAMP7和RAB7的过表达可阻断雷公藤红素对自噬的抑制作用和诱导凋亡的作用。表面等离子体共振研究证实了雷公藤红素与VAMP7和RAB7的直接结合。功能研究表明雷公藤红素处理后RAB7 GTP酶活性受到抑制。此外，雷公藤红素在小鼠附睾脂肪组织、人前脂肪细胞和脂肪细胞中诱导了类似的凋亡，但在人肝细胞中未观察到。还观察到对人原代内脏前脂肪细胞分化的抑制作用。总之，雷公藤红素通过与VAMP7和RAB7直接结合表现出自噬抑制作用，导致前脂肪细胞凋亡增加。这些结果增进了我们对雷公藤红素在治疗肥胖中的潜在应用的理解。
