Mechanism of hepertocyte differentiation by liver-enriched transcription factor network

为了确定如何确定肝脏中肝脏特异性基因的表达，我们测量了再生肝脏中肝脏特异性基因的表达。在肝部分切除术后的肝脏再生过程中，切除的肝脏必须保持正常的肝细胞功能。因此，肝切除后的肝功能较正常情况有所改善。据报道，在再生肝脏中，C/EBPβ被诱导。我们发现HNF-4基因的表达在再生肝一次下降后也会被诱导。这些结果提示，HNF-4可能参与肝脏再生过程中肝功能的维持。细胞形状对HNF-4基因表达的调节我们报道了肝细胞的细胞形状对培养的肝细胞的肝脏特异性功能的维持非常重要。而HNF-4在细胞形状依赖性的肝功能调节中起核心作用。在细胞形态到HNF-4基因的信号转导过程中，微管起着重要的作用。但微丝和中间丝不参与细胞形状依赖性的HNF-4基因表达调控。微管网络而非动态不稳定性负责细胞形状信号的传递。去除微管破坏试剂后，显著诱导HNF-4基因表达。钒酸盐通过去除试剂抑制了对HNF-4基因表达的诱导。结果表明，磷酸化/去磷酸化步骤是细胞形状诱导HNF-4的关键步骤。

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.