Inoue Yusuke, Peters Luanne L, Yim Sun Hee, Inoue Junko, Gonzalez Frank J
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
J Mol Med (Berl). 2006 Apr;84(4):334-44. doi: 10.1007/s00109-005-0013-5. Epub 2005 Dec 31.
Hepatocyte nuclear factor 4alpha (HNF4alpha) plays an important role in the maintenance of many liver-specific functions. Liver-specific HNF4alpha-null mice were used to determine whether hepatic HNF4alpha regulates blood coagulation in vivo. These mice exhibited reduced expression of hepatic coagulation factors V, IX, XI, XII, and XIIIB and a prolonged activated partial thromboplastin time but not prothrombin time. Promoter analysis of the mouse FXII and FXIIIB genes was performed to determine whether HNF4alpha directly regulates the genes encoding these coagulation factors. Sequence analysis revealed the presence of one and two HNF4alpha binding sites in the mouse FXII and FXIIIB genes, respectively. Using transient transfection and electrophoretic mobility shift analyses with the mouse FXII and FXIIIB promoters, it was established that the high levels of promoter activity were dependent on HNF4alpha binding sites and the expression of HNF4alpha. In conclusion, HNF4alpha has a critical role in blood coagulation homeostasis by directing transcription of the FXII and XIIIB genes.
肝细胞核因子4α（HNF4α）在维持多种肝脏特异性功能中发挥着重要作用。利用肝脏特异性HNF4α基因敲除小鼠来确定肝脏中的HNF4α是否在体内调节血液凝固。这些小鼠表现出肝脏凝血因子V、IX、XI、XII和XIIIB的表达降低，活化部分凝血活酶时间延长，但凝血酶原时间未延长。对小鼠FXII和FXIIIB基因进行启动子分析，以确定HNF4α是否直接调节编码这些凝血因子的基因。序列分析显示，在小鼠FXII和FXIIIB基因中分别存在一个和两个HNF4α结合位点。通过对小鼠FXII和FXIIIB启动子进行瞬时转染和电泳迁移率变动分析，确定启动子的高活性水平依赖于HNF4α结合位点和HNF4α的表达。总之，HNF4α通过指导FXII和XIIIB基因的转录在血液凝固稳态中起关键作用。
