PXR mediates mifepristone-induced hepatomegaly in mice
PXR mediates mifepristone-induced hepatomegaly in mice
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DOI：
10.1038/s41401-021-00633-4
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发表时间：
2021-03
影响因子：
8.2
通讯作者：
Xin-peng Yao;Tingying Jiao;Yiming Jiang;Shi-cheng Fan;Ying-yuan Zhao;Xiao Yang;Yue Gao;Fei Li
中科院分区：
文献类型：
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作者：
Xin-peng Yao;Tingying Jiao;Yiming Jiang;Shi-cheng Fan;Ying-yuan Zhao;Xiao Yang;Yue Gao;Fei Li
米非司酮(Mif)是一种有效的合成类固醇抗孕酮药物，广泛用于药物流产和避孕。由于其抗糖皮质激素的作用，大剂量的MIF也被用于治疗库欣综合征。体外研究表明，MIF可激活孕烷X受体(PXR)，PXR可通过激活和与YAP途径相互作用而诱导肝肿大。据报道，大剂量的MIF可引起大鼠和小鼠的肝肿大，但其潜在机制尚不清楚。在此，我们研究了PxR在Mif诱导的C57BL/6小鼠和Pxr基因敲除小鼠肝肿大中的作用。结果表明，大剂量MIF(10 0 mg · kg−1· d−1，I.P.)治疗5d后，肝细胞肿大，肝细胞增多，但低剂量Mif(5 mg · kg−1· d−1，i.p)不能诱发肝肿大。双荧光素酶报告基因分析表明，Mif能以浓度依赖的方式激活人PXR。此外，Mif还可促进PXR和YAP的核转位，并显著诱导PXR和YAP及其靶蛋白CYP3A11、CYP2B10、UGT1A1、ANKRD和CTGF的表达。而MIF(100 mg · kg−1· d−1，I.P.)未能诱导Pxr基因敲除小鼠的肝肿大以及肝细胞的增大和增殖，进一步表明Mif诱导的肝肿大是PxR依赖的。综上所述，本研究证明PXR介导的Mif诱导的小鼠肝肿大可能是通过激活YAP途径实现的。这项研究为MIF诱导的肝肿大提供了新的见解，并为PXR在肝脏增大和再生中的关键作用提供了新的证据。
Mifepristone (Mif), an effective synthetic steroidal antiprogesterone drug, is widely used for medical abortion and pregnancy prevention. Due to its anti-glucocorticoid effect, high-dose Mif is also used to treat Cushing’s syndrome. Mif was reported to active pregnane X receptor (PXR) in vitro and PXR can induce hepatomegaly via activation and interaction with yes-associated protein (YAP) pathway. High-dose Mif was reported to induce hepatomegaly in rats and mice, but the underlying mechanism remains unclear. Here, the role of PXR was studied in Mif-induced hepatomegaly in C57BL/6 mice andPxr-knockout mice. The results demonstrated that high-dose Mif (100 mg · kg−1· d−1,i.p.) treatment for 5 days significantly induced hepatomegaly with enlarged hepatocytes and promoted proliferation, but low dose of Mif (5 mg · kg−1· d−1,i.p.) cannot induce hepatomegaly. The dual-luciferase reporter gene assays showed that Mif can activate human PXR in a concentration-dependent manner. In addition, Mif could promote nuclear translocation of PXR and YAP, and significantly induced the expression of PXR, YAP, and their target proteins such as CYP3A11, CYP2B10, UGT1A1, ANKRD, and CTGF. However, Mif (100 mg · kg−1· d−1,i.p.) failed to induce hepatomegaly inPxr-knockout mice, as well as hepatocyte enlargement and proliferation, further indicating that Mif-induced hepatomegaly is PXR-dependent. In summary, this study demonstrated that PXR-mediated Mif-induced hepatomegaly in mice probably via activation of YAP pathway. This study provides new insights in Mif-induced hepatomegaly, and provides novel evidence on the crucial function of PXR in liver enlargement and regeneration.