The transcription factor Klf5 is essential for intrahepatic biliary epithelial tissue remodeling after cholestatic liver injury
The transcription factor Klf5 is essential for intrahepatic biliary epithelial tissue remodeling after cholestatic liver injury
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转录因子Klf5在胆汁淤积性肝损伤后肝内胆管上皮组织重塑中的作用
DOI：
10.1074/jbc.ra118.002372
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发表时间：
2018-04-27
影响因子：
4.8
通讯作者：
Itoh, Tohru
中科院分区：
文献类型：
--
作者：
Okada, Hajime;Yamada, Minami;Itoh, Tohru
在各种肝损伤条件下，肝内胆管上皮经历动态的组织扩张和重塑，这一过程被称为小管反应。在诱导这种组织重塑过程中有缺陷的小鼠模型更容易受到肝损伤，这表明该过程在肝再生中起着至关重要的作用。然而，调节胆管反应中胆管上皮细胞（BEC）动力学的分子机制仍不清楚。在这里，我们证明了转录因子Kruppel样因子5（Klf 5）是高度富集在小鼠肝脏BEC和发挥关键作用，特别是在胆汁淤积性损伤条件下的调节小管反应。尽管在整个肝上皮中缺乏Klf 5的小鼠，包括肝细胞和BEC（Klf 5-LKO（肝上皮特异性敲除）小鼠），在正常条件下在肝胆系统中没有表现出任何明显的表型，但它们在3，5-二乙氧羰基-1，4-二氢可力丁诱导的胆管炎后表现出胆管上皮组织重塑的显著缺陷，伴随着胆汁淤积加重和存活率降低。相反，仅在肝细胞中缺乏Klf 5的小鼠没有表现出任何这样的表型，证实了Klf 5在BEC中的特异性作用。从Klf 5-LKO小鼠肝脏分离的BEC的RNA测序分析显示Klf 5缺陷主要影响细胞周期相关基因的表达。此外，用增殖标志物Ki 67的免疫染色分析揭示Klf 5-LKO小鼠在损伤后具有显著降低的BEC增殖水平。这些结果表明Klf 5通过诱导BEC增殖并从而促进肝再生在胆管反应和胆管上皮组织扩张和重塑中起关键作用。
Under various conditions of liver injury, the intrahepatic biliary epithelium undergoes dynamic tissue expansion and remodeling, a process known as ductular reaction. Mouse models defective in inducing such a tissue-remodeling process are more susceptible to liver injury, suggesting a crucial role of this process in liver regeneration. However, the molecular mechanisms regulating the biliary epithelial cell (BEC) dynamics in the ductular reaction remain largely unclear. Here, we demonstrate that the transcription factor Kruppel-like factor 5 (Klf5) is highly enriched in mouse liver BECs and plays a key role in regulating the ductular reaction, specifically under cholestatic injury conditions. Although mice lacking Klf5 in the entire liver epithelium, including both hepatocytes and BECs (Klf5-LKO (liver epithelial-specific knockout) mice), did not exhibit any apparent phenotype in the hepatobiliary system under normal conditions, they exhibited significant defects in biliary epithelial tissue remodeling upon 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced cholangitis, concomitantly with exacerbated cholestasis and reduced survival rate. In contrast, mice lacking Klf5 solely in hepatocytes did not exhibit any such phenotypes, confirming Klf5's specific role in BECs. RNA-sequencing analyses of BECs isolated from the Klf5-LKO mouse livers revealed that the Klf5 deficiency primarily affected expression of cell cycle-related genes. Moreover, immunostaining analysis with the proliferation marker Ki67 disclosed that the Klf5-LKO mice had significantly reduced BEC proliferation levels upon injury. These results indicate that Klf5 plays a critical role in the ductular reaction and biliary epithelial tissue expansion and remodeling by inducing BEC proliferation and thereby contributing to liver regeneration.