Mechanism of hepertocyte differentiation by liver-enriched transcription factor network

肝脏特异性基因表达的分子机制的体内研究为了确定如何确定肝脏特异性基因在肝脏中的表达，我们测量了再生肝脏中肝脏特异性基因的表达。在肝部分切除后的肝再生过程中，肝切除后的肝脏必须保持正常的肝细胞功能。因此，与平时相比，肝切除可以增强肝功能。在再生肝脏中，有报道诱导C/EBPβ。我们还发现，在再生肝中，HNF-4基因的表达在一次下降后也被诱导。这些结果提示，HNF-4可能参与了肝再生过程中肝脏功能的维持。细胞形态对HNF-4基因表达的调节我们报道了肝细胞的细胞形态对维持肝细胞的肝特异性功能非常重要。HNF-4在细胞形态依赖的肝功能调节中起核心作用。在从细胞形态到HNF-4基因的信号转导中，微管起着重要作用。但微丝和中间丝不参与HNF-4基因表达的细胞形态依赖性调控。微管网络而不是动态不稳定性负责细胞形态信号的传递。去除微管阻断剂后，HNF-4基因表达明显增强。钒酸盐可通过去除试剂抑制HNF-4基因表达的诱导。结果表明，磷酸化/去磷酸化步骤在细胞形态诱导HNF-4的过程中起关键作用。

in vivo study of molecular mechanism of liver-specific gene expressionIn order to determine how to determine liver-specific gene expression in liver, we measured liver-specific gene expression in regenerating liver. During regeneration of liver after partial hepatectomy, hepatectomized liver has to keep normal hepatocyte functions. Therefore, the hepatectomized liver enhances the liver-function as compared to usual. In regenerating liver, C/EBPβ is reported to be induced. And we found that HNF-4 gene expression was also induced after once dropped in regenerating liver. These results suggested that HNF-4 might be involved in maintenance of liver-function in regenerating liver.Regulation of HNF-4 gene expression by cell shapeWe reported that cell shape of hepatocytes was very important of maintenance of liver-specific function in cultured hepatocytes. And HNF-4 plays central role in cell shape dependent regulation of liver function. In signal transduction from cell shape to HNF-4 gene, microtuble was important. But microfilament and intermediate filament were not involved in cell shape-dependent regulation of HNF-4 gene expression. And microtuble network but not dynamic instability was responsible for the transmission of cell shape signal. After removal of microtuble disruption reagent, HNF-4 gene expression was markedly induced. Vanadate inhibited the induction of HNF-4 gene expression by the removal of the reagent. The results suggested that phosphorylation/dephosphorylation steps were crucial the HNF-4 induction by cell shape.