Role of hepatocyte nuclear factor 4α in control of blood coagulation factor gene expression

Hepatocyte nuclear factor 4 alpha (HNF4 alpha) plays an important role in the maintenance of many liver-specific functions. Liver-specific HNF alpha-null mice were used to determine whether hepatic HNF4 alpha 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 HNF4 alpha directly regulates the genes encoding these coagulation factors. Sequence analysis revealed the presence of one and two HNF4 alpha 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 HNF4a binding sites and the expression of HNF4 alpha. In conclusion, HNF4 alpha has a critical role in blood coagulation homeostasis by directing transcription of the FXII and XIIIB genes.