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)

背景：肝细胞核因子4α（HNF4α）在调节细胞因子诱导的炎症反应中起重要作用。本研究旨在探讨HNF4α在脂多糖/ D -半乳糖胺（LPS / D - GalN）诱导的暴发性肝衰竭（FHF）发展中的作用。 方法：通过在小鼠腹腔内同时注射LPS / D - GalN建立FHF模型。在注射LPS / D - GalN前3天，采用基于流体动力学的方法经尾静脉注射HNF4α短发夹干扰RNA表达质粒或生理盐水。随后评估肝损伤程度和累计存活率。 结果：在注射LPS / D - GalN后的早期阶段，HNF4α的表达增加。抑制HNF4α的表达可降低血清丙氨酸氨基转移酶和天冬氨酸氨基转移酶水平，减轻组织学损伤，并提高FHF小鼠的存活率。此外，在FHF小鼠中抑制HNF4α表达时，血清和肝脏肿瘤坏死因子α的表达均受到抑制。 结论：抑制HNF4α表达可保护小鼠免受LPS / D - GalN诱导的FHF，但其确切机制需要进一步研究。（《国际肝胆胰疾病杂志》2012年；11：624 - 629）