Cellular Location of HNF4α is Linked With Terminal Liver Failure in Humans

Hepatocyte nuclear factor 4 alpha (HNF4 alpha) is a transcription factor that plays a critical role in hepatocyte function, and HNF4 alpha-based reprogramming corrects terminal liver failure in rats with chronic liver disease. In the livers of patients with advanced cirrhosis, HNF4 alpha RNA expression levels decrease as hepatic function deteriorates, and protein expression is found in the cytoplasm. These findings could explain impaired hepatic function in patients with degenerative liver disease. In this study, we analyzed HNF4 alpha localization and the pathways involved in post-translational modification of HNF4 alpha in human hepatocytes from patients with decompensated liver function. RNA-sequencing analysis revealed that AKT-related pathways, specifically phospho-AKT, is down-regulated in cirrhotic hepatocytes from patients with terminal failure, in whom nuclear levels of HNF4 alpha were significantly reduced, and cytoplasmic expression of HNF4 alpha was increased. cMET was also significantly reduced in failing hepatocytes. Moreover, metabolic profiling showed a glycolytic phenotype in failing human hepatocytes. The contribution of cMET and phospho-AKT to nuclear localization of HNF4 alpha was confirmed using Spearman's rank correlation test and pathway analysis, and further correlated with hepatic dysfunction by principal component analysis. HNF4 alpha acetylation, a posttranslational modification important for nuclear retention, was also significantly reduced in failing human hepatocytes when compared with normal controls. Conclusion: These results suggest that the alterations in the cMET-AKT pathway directly correlate with HNF4 alpha localization and level of hepatocyte dysfunction. This study suggests that manipulation of HNF4 alpha and pathways involved in HNF4 alpha posttranslational modification may restore hepatocyte function in patients with terminal liver failure.