Hepatocyte-specific deletion of farnesoid X receptor delays but does not inhibit liver regeneration after partial hepatectomy in mice.
Hepatocyte-specific deletion of farnesoid X receptor delays but does not inhibit liver regeneration after partial hepatectomy in mice.
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DOI：
10.1002/hep.25918
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发表时间：
2012-12
期刊：
影响因子：
13.5
通讯作者：
Apte, Udayan
中科院分区：
文献类型：
--
作者：
Borude, Prachi;Edwards, Genea;Walesky, Chad;Li, Feng;Ma, Xiaochao;Kong, Bo;Guo, Grace L.;Apte, Udayan
法尼醇X受体（FXR）是一种主要的胆汁酸敏感核受体，也在刺激肝再生中发挥作用。FXR的整体缺失导致部分肝切除术（PHX）后肝再生的显著抑制。FXR在肝脏和肠道中表达，最近的ChIP-seq分析表明FXR以组织特异性方式调节不同的基因组。这些数据提出了关于肝和肠FXR在肝再生调节中的相对贡献的问题。我们研究了肝细胞特异性FXR敲除（hepFXR-KO）小鼠PHX后0至14天的肝再生。尽管hepFXR-KO小鼠中肝脏再生长的总体动力学不受影响，但与Cre对照小鼠相比，在hepFXR-KO小鼠中观察到PHX后第2天至第3天的肝细胞增殖峰值延迟。真实的时间PCR、蛋白质印迹和co-IP研究显示，PHX后hepFXR-KO小鼠中Cyclin D1表达降低，Cyclin D1与CDK 4的相关性降低，与pRb磷酸化降低和hepFXR-KO肝脏中细胞增殖延迟相关。hepFXR-KO小鼠还表现出PHX后急性肝脂肪积累的延迟，这与细胞周期的调节有关。此外，在hepFXR-KO小鼠中观察到HGF启动的信号传导（包括AKT、c-myc和ERK-1/2途径）的显著延迟。肝胆汁酸的UPLC-质谱分析表明hepFXR-KO和对照小鼠中胆汁酸水平无差异。结论：肝FXR的缺失并不能完全抑制PHX后的肝再生，但会延迟PHX后继发于延迟的Cyclin D1激活的肝再生。
Farnesoid X Receptor (FXR), the primary bile acid-sensing nuclear receptor, also plays a role in stimulation of liver regeneration. Whole body deletion of FXR results in significant inhibition of liver regeneration after partial hepatectomy (PHX). FXR is expressed in liver and intestine and recent ChIP-seq analysis indicates that FXR regulates distinct set of genes in a tissue-specific manner. These data raise the question about relative contribution of hepatic and intestinal FXR in regulation of liver regeneration. We studied liver regeneration after PHX in hepatocyte-specific FXR knockout (hepFXR-KO) mice over a time course of 0 to 14 days. Whereas the overall kinetics of liver regrowth in hepFXR-KO mice was unaffected, a delay in peak hepatocyte proliferation from day 2 to day 3 after PHX was observed in the hepFXR-KO mice as compared to Cre- control mice. Real Time PCR, Western blot and co-IP studies revealed decreased Cyclin D1 expression and decreased association of Cyclin D1 with CDK4 in hepFXR-KO mice after PHX, correlating with decreased phosphorylation of pRb and delayed cell proliferation in the hepFXR-KO livers. The hepFXR-KO mice also exhibited delay in acute hepatic fat accumulation following PHX, which is associated with regulation of cell cycle. Further, a significant delay in HGF-initiated signaling, including AKT, c-myc and ERK-1/2 pathways, was observed in hepFXR-KO mice. UPLC-mass spectroscopy analysis of hepatic bile acids indicated no difference in levels of bile acids in hepFXR-KO and control mice. In Conclusion, deletion of hepatic FXR did not completely inhibit but delays liver regeneration after PHX secondary to delayed Cyclin D1 activation.
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影响因子：
13.5
作者：
Apte, Udayan;Gkretsi, Vasiliki;Bowen, William C.;Mars, Wendy M.;Luo, Jian-Hua;Donthamsetty, Shashikiran;Orr, Ann;Monga, Satdarshan P. S.;Wu, Chuanyue;Michalopoulos, George K.
通讯作者：
Michalopoulos, George K.
影响因子：
13.5
作者：
Fausto, N;Campbell, JS;Riehle, KJ
通讯作者：
Riehle, KJ
DOI：
10.1124/jpet.108.144600
发表时间：
2009-01-01
影响因子：
3.5
作者：
Kong, Bo;Luyendyk, James P.;Guo, Grace L.
通讯作者：
Guo, Grace L.
影响因子：
2.3
作者：
Trauner, Michael;Claudel, Thierry;Wagner, Martin
通讯作者：
Wagner, Martin
影响因子：
8
作者：
Seol, DW;Chen, QY;Zarnegar, R
通讯作者：
Zarnegar, R