Pregnane X Receptor Regulates Liver Size and Liver Cell Fate by Yes-Associated Protein Activation in Mice.
Pregnane X Receptor Regulates Liver Size and Liver Cell Fate by Yes-Associated Protein Activation in Mice.
复制标题
Pregnane X 受体通过 Yes 相关蛋白激活调节小鼠肝脏大小和肝细胞命运。
DOI：
10.1002/hep.30131
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发表时间：
2019-01
期刊：
影响因子：
--
通讯作者：
Bi H
中科院分区：
文献类型：
--
作者：
Jiang Y;Feng D;Ma X;Fan S;Gao Y;Fu K;Wang Y;Sun J;Yao X;Liu C;Zhang H;Xu L;Liu A;Gonzalez FJ;Yang Y;Gao B;Huang M;Bi H
孕烷X受体(PXR)是一种控制异种和内生代谢的核受体，它的激活被认为是导致肝脏增大的原因，但对PXR引起的肝肿大的分子信号和细胞类型尚不清楚。在这项研究中，在几个品系的转基因小鼠和动物模型中，评估了PXR激活对肝脏增大和细胞变化的影响。用AAV-TBG-Cre处理的Rosa26EYFP小鼠或Sox9-CreERT、Rosa26EYFP小鼠进行谱系标记，并用PxR缺失的小鼠或AAV Yap shRNA处理的小鼠确认PxR或YAP的作用。选择性PXR激活剂通过增加细胞大小、诱导再生杂交肝细胞(HybHP)重编程、促进肝细胞和HybHP增殖，在野生型和PXR人源化小鼠中诱导肝脏增大和加速再生，而在PXR缺失小鼠中则不诱导。从机制上讲，PXR与YAP相互作用，PXR激活导致YAP核转位。阻断YAP可抑制PXR诱导的小鼠肝脏肿大。这些发现揭示了PXR通过激活YAP信号通路来扩大肝脏体积和改变肝细胞命运的新功能。这些结果对理解PXR的生理功能具有重要意义，并提示了控制肝脏大小和肝细胞命运的可能性。
Activation of pregnane X receptor (PXR), a nuclear receptor that controls xenobiotic and endobiotic metabolism, is known to induce liver enlargement, but the molecular signals and the cell types responding to PXR-induced hepatomegaly remain unknown. In this study, the effect of PXR activation on liver enlargement and cell change was evaluated in several strains of genetically-modified mice and animal models. Lineage labelling using AAV-Tbg-Cre-treated Rosa26EYFP mice or Sox9-CreERT, Rosa26EYFP mice was performed and Pxr-null mice or AAV Yap shRNA-treated mice were used to confirm the role of PXR or YAP. Treatment with selective PXR activators induced liver enlargement and accelerated regeneration in wild-type and PXR-humanized mice but not in Pxr-null mice by increase of cell size, induction of a regenerative hybrid hepatocyte (HybHP) reprogramming, and promotion of hepatocyte and HybHP proliferation. Mechanistically, PXR interacted with yes-associated protein (YAP) and PXR activation induced nuclear translocation of YAP. Blockade of YAP abolished PXR-induced liver enlargement in mice. These findings revealed a novel function of PXR in enlarging liver size and changing liver cell fate via activation of the YAP signalling pathway. These results have implications for understanding the physiological functions of PXR and suggest the potential for manipulation of liver size and liver cell fate.
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影响因子：
15.9
作者：
Mu, Xueru;Espanol-Suner, Regina;Schwabe, Robert F.
通讯作者：
Schwabe, Robert F.
影响因子：
64.5
作者：
Dong, Jixin;Feldmann, Georg;Pan, Duojia
通讯作者：
Pan, Duojia
DOI：
10.1038/nrm3591
发表时间：
2013-06
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
15.9
作者：
Kim, Wantae;Khan, Sanjoy Kumar;Yang, Yingzi
通讯作者：
Yang, Yingzi
影响因子：
4.5
作者：
CRAMPTON, RF;GRAY, TJB;PARKE, DV
通讯作者：
PARKE, DV