Celastrol targets adenylyl cyclase-associated protein 1 to reduce macrophages-mediated inflammation and ameliorates high fat diet-induced metabolic syndrome in mice.
Celastrol targets adenylyl cyclase-associated protein 1 to reduce macrophages-mediated inflammation and ameliorates high fat diet-induced metabolic syndrome in mice.
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雷公藤红素靶向腺苷酸环化酶相关蛋白 1，减少巨噬细胞介导的炎症并改善高脂肪饮食诱导的小鼠代谢综合征
DOI：
10.1016/j.apsb.2020.12.008
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发表时间：
2021-05
期刊：
影响因子：
--
通讯作者：
Sun Y
中科院分区：
文献类型：
--
作者：
Zhu Y;Wan N;Shan X;Deng G;Xu Q;Ye H;Sun Y
代谢综合征是一种分子机制尚不清楚的代谢紊乱的聚类。越来越多的研究发现代谢综合征的发病和进展与炎症密切相关。在这里，我们报道了雷公藤红素，一种传统的中药，可以通过抑制抵抗素诱导的炎症来改善高脂肪饮食诱导的代谢综合征。其机制是通过与腺苷酸环化酶相关蛋白1 （CAP1）结合，抑制CAP1与抵抗素的相互作用，从而抑制环腺苷酸单磷酸(cAMP) -蛋白激酶A (PKA) -核因子κ b （NF-κB）信号通路，改善高脂饮食诱导的小鼠代谢综合征。巨噬细胞中CAP1的下调消除了抵抗素介导的炎症活性。相反，巨噬细胞中CAP1的过表达加重了炎症。综上所述，我们的研究确定了直接靶向巨噬细胞中CAP1的celastrol可能是治疗炎症性代谢疾病（如代谢综合征）的有希望的候选药物。在肥胖中，脂肪组织产生抵抗素，抵抗素与巨噬细胞上的CAP1结合，激活cAMP-PKA-NF -κB信号通路，促进促炎细胞因子表达。这些因素进一步加重炎症、胰岛素抵抗和肝脂肪变性。雷公藤红素通过与CAP1结合并抑制其与抵抗素的相互作用改善代谢综合征。
Metabolic syndrome is a clustering of metabolic disorder with unclear molecular mechanism. Increasing studies have found that the pathogenesis and progression of metabolic syndrome are closely related to inflammation. Here, we report celastrol, a traditional Chinese medicine, can improve high fat diet-induced metabolic syndrome through suppressing resistin-induced inflammation. Mechanistically, celastrol binds to adenylyl cyclase associated protein 1 (CAP1) and inhibits the interaction between CAP1 and resistin, which restrains the cyclic adenylate monophosphate (cAMP)–protein kinase A (PKA)–nuclear factor kappa-B (NF-κB) signaling pathway and ameliorates high fat diet-induced murine metabolic syndrome. Knockdown of CAP1 in macrophages abrogated the resistin-mediated inflammatory activity. In contrast, overexpression of CAP1 in macrophages aggravated inflammation. Taken together, our study identifies celastrol, which directly targets CAP1 in macrophages, might be a promising drug candidate for the treatment of inflammatory metabolic diseases, such as metabolic syndrome. In obesity, adipose tissue generates resistin, which binds to CAP1 on macrophages and activates the cAMP–PKA–NF-κB signaling pathway and promotes proinflammatory cytokines expression. These factors further aggravate inflammation, insulin resistance, and hepatic steatosis. Celastrol ameliorates metabolic syndrome via binding to CAP1 and inhibiting its interaction with resistin.
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