Celastrol-regulated gut microbiota and bile acid metabolism alleviate hepatocellular carcinoma proliferation by regulating the interaction between FXR and RXRα in vivo and in vitro.
Celastrol-regulated gut microbiota and bile acid metabolism alleviate hepatocellular carcinoma proliferation by regulating the interaction between FXR and RXRα in vivo and in vitro.
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雷公藤红素调节肠道微生物群和胆汁酸代谢通过调节体内和体外 FXR 和 RXRα 之间的相互作用来减轻肝细胞癌增殖
DOI：
10.3389/fphar.2023.1124240
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发表时间：
2023
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
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作者：
雷公藤红素是从雷公藤科雷公藤属植物雷公藤中提取的一种三萜类化合物，具有良好的抗癌活性。本研究旨在阐明雷公藤红素通过肠道微生物群调节胆汁酸代谢和下游信号传导介导的肝细胞癌（HCC）缓解的间接机制。在此，我们构建了大鼠原位肝癌模型，并进行了16 S rDNA测序和UPLC-MS分析。结果表明，雷公藤红素可以调节肠道细菌;抑制脆弱拟杆菌的丰度;提高胆汁酸甘氨熊去氧胆酸（GUDCA）的水平;并减轻HCC。我们发现GUDCA抑制HepG 2细胞的增殖，并诱导mTOR/S6 K1通路相关的细胞周期G 0/G1期阻滞。使用分子模拟、Co-IP和免疫荧光测定的进一步分析显示，GUDCA与法尼醇X受体（FXR）结合，并调节FXR与维甲酸X受体a（RXRα）的相互作用。使用FXR突变体的转染实验证实FXR对于GUCDA介导的HCC细胞增殖的抑制是必需的。最后，动物实验表明，雷公藤红素/GUDCA组合治疗减轻了雷公藤红素单独治疗对体重减轻的不利影响，并提高了HCC大鼠的存活率。总之，本研究的结果表明雷公藤红素对HCC发挥缓解作用，部分是通过调节B。fragilis-GUDCA-FXR/RXRα-mTOR轴。
Celastrol, a triterpene derived from Thunder God Vine (Tripterygium wilfordii Hook f; Celastraceae), a traditional Chinese herb, has promising anticancer activity. The present study aimed to elucidate an indirect mechanism of celastrol-mediated alleviation of hepatocellular carcinoma (HCC) via gut microbiota-regulated bile acid metabolism and downstream signaling. Here, we constructed a rat model of orthotopic HCC and performed 16S rDNA sequencing and UPLC-MS analysis. The results showed that celastrol could regulate gut bacteria; suppress the abundance of Bacteroides fragilis; raise the levels of glycoursodeoxycholic acid (GUDCA), a bile acid; and alleviate HCC. We found that GUDCA suppressed cellular proliferation and induced the arrest of mTOR/S6K1 pathway-associated cell cycle G0/G1 phase in HepG2 cells. Further analyses using molecular simulations, Co-IP, and immunofluorescence assays revealed that GUDCA binds to farnesoid X receptor (FXR) and regulates the interaction of FXR with retinoid X receptor a (RXRα). Transfection experiments using the FXR mutant confirmed that FXR is essential for GUCDA-mediated suppression of HCC cellular proliferation. Finally, animal experiments showed that the treatment with the combination of celastrol/GUDCA alleviated the adverse effects of celastrol alone treatment on body weight loss and improved survival in rats with HCC. In conclusion, the findings of this study suggest that celastrol exerts an alleviating effect on HCC, in part via regulation of the B. fragilis-GUDCA-FXR/RXRα-mTOR axis.
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影响因子：
--
作者：
Shinji S;Ueda Y;Yamada T;Koizumi M;Yokoyama Y;Takahashi G;Hotta M;Iwai T;Hara K;Takeda K;Okusa M;Kan H;Uchida E
通讯作者：
Uchida E
影响因子：
3.9
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16
作者：
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Zhang XK
影响因子：
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作者：
Chang, Wei;He, Wei;Wei, Wei
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