Role of hepatocyte nuclear factor 4alpha in control of blood coagulation factor gene expression.
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.
Inoue
Yusuke
Y
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Peters
Luanne L
LL
Yim
Sun Hee
SH
Inoue
Junko
J
Gonzalez
Frank J
FJ
D000818:Animals; D001777:Blood Coagulation / Q000235:genetics; D001779:Blood Coagulation Factors / Q000235:genetics*; D015536:Down-Regulation; D005164:Factor IX / Q000378:metabolism; D005165:Factor V / Q000378:metabolism; D005172:Factor XI / Q000378:metabolism; D005174:Factor XII / Q000378:metabolism; D005176:Factor XIII / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000502:physiology; D051557:Hepatocyte Nuclear Factor 4 / Q000172:deficiency / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009928:Organ Specificity / Q000235:genetics; D010314:Partial Thromboplastin Time; D011401:Promoter Regions, Genetic; D050436:Regulatory Elements, Transcriptional; D014914:Whole Blood Coagulation Time
D001779:Blood Coagulation Factors; D051557:Hepatocyte Nuclear Factor 4; D005165:Factor V; D005164:Factor IX; D005174:Factor XII; D005172:Factor XI; D005176:Factor XIII; C054380:factor XIIIb