Conditional loss of heparin-binding EGF-like growth factor results in enhanced liver fibrosis after bile duct ligation in mice.
Conditional loss of heparin-binding EGF-like growth factor results in enhanced liver fibrosis after bile duct ligation in mice.
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DOI：
10.1016/j.bbrc.2013.05.097
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发表时间：
2013-07
影响因子：
3.1
通讯作者：
Takayo Takemura;Y. Yoshida;S. Kiso;Takashi Kizu;Kunimaro Furuta;Hisao Ezaki;Mina Hamano;M. Egawa;Norihiro Chatani;Y. Kamada;Y. Imai;S. Higashiyama;R. Iwamoto;E. Mekada;T. Takehara
中科院分区：
文献类型：
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作者：
Takayo Takemura;Y. Yoshida;S. Kiso;Takashi Kizu;Kunimaro Furuta;Hisao Ezaki;Mina Hamano;M. Egawa;Norihiro Chatani;Y. Kamada;Y. Imai;S. Higashiyama;R. Iwamoto;E. Mekada;T. Takehara
我们的目的是评估肝素结合EGF样生长因子（HB-EGF）在人类和小鼠肝纤维化中的参与，并阐明HB-EGF缺乏对条件性HB-EGF敲除（KO）小鼠胆汁淤积性肝纤维化的影响。我们首次证明，HB-EGF的基因表达与人纤维化肝脏中的胶原蛋白的基因表达呈正相关，并且在胆管结扎（BDL）诱导的小鼠纤维化肝脏中增加。然后，我们使用干扰素诱导的Mx-1启动子驱动的Cre重组酶转基因产生条件性HB-EGF敲除（KO）小鼠，并对野生型（WT）和KO小鼠进行BDL。与WT小鼠相比，BDL后KO小鼠表现出增强的肝纤维化，胶原蛋白表达增加。最后，我们使用小鼠肝星状细胞（HSC）来检测HB-EGF在这些细胞活化中的作用，并显示HB-EGF拮抗TGF-β诱导的小鼠原代HSC中胶原基因表达。有趣的是，HB-EGF并不能阻止TGF-β诱导的Smad 3的核积累，但确实导致了Smad转录辅阻遏物TG相互作用因子的稳定。总之，我们的数据表明HB-EGF在胆汁淤积性肝纤维化中可能具有保护作用。
Our aims were to evaluate the involvement of heparin-binding EGF-like growth factor (HB-EGF) in liver fibrogenesis of humans and mice and to elucidate the effect of HB-EGF deficiency on cholestatic liver fibrosis using conditional HB-EGF knockout (KO) mice. We first demonstrated that gene expression of HB-EGF had a positive significant correlation with that of collagen in human fibrotic livers, and was increased in bile duct ligation (BDL)-induced fibrotic livers in mouse. We then generated conditional HB-EGF knockout (KO) mice using the interferon inducibleMx-1promoter driven Cre recombinase transgene and wild type (WT) and KO mice were subjected to BDL. After BDL, KO mice exhibited enhanced liver fibrosis with increased expression of collagen, compared with WT mice. Finally, we used mouse hepatic stellate cells (HSCs) to examine the role of HB-EGF in the activation of these cells and showed that HB-EGF antagonized TGF-β-induced gene expression of collagen in mouse primary HSCs. Interestingly, HB-EGF did not prevent the TGF-β-induced nuclear accumulation of Smad3, but did lead to stabilization of the Smad transcriptional co-repressor TG-interacting factor. In conclusion, our data suggest a possible protective role of HB-EGF in cholestatic liver fibrosis.