Inhibiting the expression of hepatocyte nuclear factor 4 alpha attenuates lipopolysaccharide/D-galactosamine-induced fulminant hepatic failure in mice

BACKGROUND: Hepatocyte nuclear factor 4 alpha (HNF4 alpha) plays an important role in regulating cytokine-induced inflammatory responses. This study aimed to investigate the role of HNF4 alpha in the development of fulminant hepatic failure (FHF) induced by lipopolysaccharide/D-galactosamine (LPS/D-GalN). METHODS: The FHF model was induced by simultaneous intraperitoneal injection of LPS/D-GalN in mice. Three days prior to LPS/D-GalN administration, HNF4 alpha short-hairpin interfering RNA expression plasmid or physiological saline was injected via the tail vein with a hydrodynamics-based procedure. The degree of hepatic damage and cumulative survival rate were subsequently assessed. RESULTS: The expression of HNF4 alpha was increased in the early stage after LPS/D-GalN administration. Inhibiting the expression of HNF4 alpha reduced serum levels of alanine aminotransferase and aspartate aminotransferase, alleviated histological injury, and improved the survival of mice with FHF. In addition, both serum and hepatic tumor necrosis factor alpha expression were suppressed when HNF4 alpha expression was inhibited in mice with FHF. CONCLUSION: Inhibiting HNF4 alpha expression protects mice from FHF induced by LPS/D-GalN, but the exact mechanism behind this needs further investigation. (Hepatobiliary Pancreat Dis Int 2012;11:624-629)