PLX292228

GSE134422: HNF4 nuclear localization correlates with the clinical progression of terminal hepatic failure in humans

• Organsim human
• Type RNASEQ
• Target gene
• Project ARCHS4

HNF4 is a transcription factor that plays a critical role in terminal hepatocyte failure. HNF4-based reprogramming therapy can correct terminal liver failure in rats and humans. As liver disease progresses, HNF4 expression decreases in the nuclei of hepatocytes, leading to impaired regulation and hepatic function. Post-translational modifications (PTMs) are a fundamental regulatory mechanism of protein function and localization. In this study, we analyzed HNF4 localization and pathways involved in HNF4 PTMs in human hepatocytes at different stages of decompensated liver function upon Child-Pugh classification. RNA-seq analysis revealed that HNF4 and the PTMs-pathway related to AKT are down-regulation in cirrhotic hepatocytes with terminal failure. These findings were confirmed by protein expression, where the HNF4 nuclear levels are significantly reduced in ChildPugh B and C hepatocytes, whereas cytoplasmic expression of HNF4 was increased. Moreover, cMET and phospho-AKT were significantly reduced in ChildPugh B and C hepatocytes. The association and statistical contribution of cMET and phospho-AKT to the nuclear localization of HNF4 were confirmed by Spearmans rank correlation test and pathway analysis. Principal component analysis was used to characterize the protein profiles related to the degree of liver dysfunction. Additionally, HNF4 acetylation was significantly reduced in failing human hepatocytes when compared to normal controls, demonstrating a significant correlation to the degree of hepatic function. Conclusion: These results suggest that the alterations in the cMET-AKT pathway directly correlate to HNF4 localization and the level of hepatic dysfunction. In conclusion, this study has therapeutic implications and suggests that manipulation of these pathways may restore hepatocyte function in terminal liver failure. SOURCE: Sarah,J,Hainer (sarah.hainer@pitt.edu) - Hainer Lab University of Pittsburgh