The Role of Hypoxia-Inducible Factor 1 Alpha in Acute-on-Chronic Liver Failure

Acute-on-chronic liver failure (ACLF) is associated with increased mortality. Specific therapy options are limited. Hypoxia-inducible factor 1 alpha (HIF-1 alpha) has been linked to the pathogenesis of chronic liver disease (CLD), but the role of HIF-1 alpha in ACLF is poorly understood. In the current study, different etiologies of CLD and precipitating events triggering ACLF were used in four rodent models. HIF-1 alpha expression and the intracellular pathway of HIF-1 alpha induction were investigated using real-time quantitative PCR. The results were verified by Western blotting and immunohistochemistry for extrahepatic HIF-1 alpha expression using transcriptome analysis. Exploratory immunohistochemical staining was performed to assess HIF-1 alpha in human liver tissue. Intrahepatic HIF-1 alpha expression was significantly increased in all animals with ACLF, regardless of the underlying etiology of CLD or the precipitating event. The induction of HIF-1 alpha was accompanied by the increased mRNA expression of NFkB1 and STAT3 and resulted in a marked elevation of mRNA levels of its downstream genes. Extrahepatic HIF-1 alpha expression was not elevated. In human liver tissue samples, HIF-1 alpha expression was elevated in CLD and ACLF. Increased intrahepatic HIF-1 alpha expression seems to play an important role in the pathogenesis of ACLF, and future studies are pending to investigate the role of therapeutic HIF inhibitors in ACLF.