Impaired hepatocyte maturation, abnormal expression of biliary transcription factors and liver fibrosis in C/EBPα (Cebpa)-knockout mice
Impaired hepatocyte maturation, abnormal expression of biliary transcription factors and liver fibrosis in C/EBPα (Cebpa)-knockout mice
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DOI：
10.14670/hh-29.107
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发表时间：
2014-01-01
影响因子：
2
通讯作者：
Shiojiri, Nobuyoshi
中科院分区：
文献类型：
--
作者：
Akai, Yusuke;Oitate, Takeshi;Shiojiri, Nobuyoshi
C/EBPα基因(CEBPA)在小鼠体内失活，不仅导致肝细胞成熟受阻，还可诱导肝实质中的假腺体结构。本研究旨在确定控制分化为肝细胞和胆管上皮细胞的其他转录因子的表达是如何受到影响的，以及包括胆汁和血管系统在内的肝脏结构在胚胎敲除肝脏中是如何被紊乱的。组织化学分析表明，HNF1α和HNF4α在基因敲除的肝脏中的表达是异质性的，并不是所有的实质细胞(假腺体)都表达这些转录因子，而野生型肝脏的实质细胞都表达这些转录因子。SOX9只在野生型肝脏的胆管细胞中表达，在敲除的肝脏的许多假腺细胞中都能检测到。虽然假腺体细胞通常共表达SOX9和HNF1α/HNF4α，但在实质内有时可检测到表达SOX9但不表达HNF1α/HNF4α的胆管细胞。门静脉周围胆管结构与实质的分离以及转录因子和胆道黏附分子EP-CAM的表达异常。这些结果提示CEBPA基因的失活导致肝脏富集型转录因子或胆汁转录因子的不稳定表达和EP-CAM的表达升高，这可能导致敲除的肝脏中胆管形态发生的异常。实质成熟受损导致PECAM-1、结蛋白和Foxf1表达增加，提示实质成熟在非实质细胞(星状细胞和窦状内皮细胞)的正常组织发生中起重要作用。
Inactivation of the C/EBP alpha gene (Cebpa) in the mouse not only causes impaired hepatocyte maturation, but also induces pseudoglandular structures in the liver parenchyma. The present study was undertaken to determine how the expression of other transcription factors controlling differentiation into hepatocytes and biliary epithelial cells is affected, and how the hepatic architecture, including the bile and vascular systems, is disordered in the fetal knockout liver. Histochemical analyses demonstrated that the expression of HNF1 alpha and HNF4 alpha was heterogeneous in the knockout liver, and that not all parenchymal cells (pseudoglandular) expressed these transcription factors, whereas parenchymal cells in the wild-type liver homogeneously expressed these transcription factors. SOX9, which was expressed only in biliary cells in the wild-type liver, was detectable in many pseudoglandular cells of the knockout liver. Although the pseudoglandular cells often coexpressed SOX9 and HNF1 alpha/HNF4 alpha, cells expressing SOX9 but not expressing HNF1 alpha/HNF4 alpha (biliary cells) were sometimes detectable in the parenchyma. Periportal biliary structures were abnormal in their segregation from the parenchyma and in their expression of the transcription factors and Ep-CAM, a biliary adhesion molecule. These results suggest that the inactivation of the Cebpa gene causes unstable expression of liver-enriched transcription factors or biliary transcription factors and elevated expression of Ep-CAM, which may lead to abnormal biliary morphogenesis in the knockout liver. The impaired maturation of the parenchyma caused elevated expression of PECAM-1, desmin and Foxf1, suggesting that the maturation of the parenchyma plays an important role in the normal histogenesis of nonparenchymal cells (stellate cells and sinusoidal endothelial cells).