Induction Of Functional Activity Of Hepatocyte By Hepatocyte Nuclear Factor 4 In Vitro And In Vivo

Background and Objective: Hepatocyte transplantation (HCT) may serve as an treatment for patients with life-threatening liver disease. Currently, the shortages of the donor hepatocytes for HCT include incompetent liver-specific functions. Hepatocyte nuclear factor 4 (HNF4) acts as a positive transcriptional regulator of maintaining liver-specific functions and regulating hepatocyte differentiation. Now we investigated the Induction of Functional Activity of Hepatocyte by HNF4 in vitro and in vivo.Methods: we compared the expression of HNF4αand some liver-specific genes in different hepatocytes and constructed the recombinant adenoviruses expressing HNF4α(AdHNF4α). Then, we investigated the effect of HNF4αon functional activity of human hepatoma cells and mouse ES cells in vitro using AdHNF4α. Finally we transplanted HepG2 modified by HNF4α(HepG2-HNF4α) into mice with acute hepatic failure, so as to elucidate the therapeutic effect of HepG2-HNF4αon acute hepatic failure.Results: HNF4αexpression was correlated with the level of hepatic differentiation and the expression of some liver-specific genes was positively correlated with HNF4αexpression. Hepatoma cells transfected with HNF4αrestored the differentiated gene expressions. Upregulation of HNF4αexpression in mouse ES cells could enhance the expression of some liver-specific genes and the liver functions such as glycogen storage, and ICG metabolism. HepG2-HNF4αcould ameliorate liver functions markedly and increase the survival percentage of mice with acute hepatic failure significantly in vivo.Conclusion: Upregulation of HNF4αexpression in donor hepatocytes could enhance some liver specific functions. HNF4αmodified donor hepatocytes may represent a useful strategy for the treatment of severe liver disease.