Progressive loss of hepatocyte nuclear factor 4 alpha activity in chronic liver diseases in humans

Background and Aims Hepatocyte nuclear factor 4 alpha (HNF4 alpha) is indispensable for hepatocyte differentiation and critical for maintaining liver health. Here, we demonstrate that loss of HNF4 alpha activity is a crucial step in the pathogenesis of chronic liver diseases (CLDs) that lead to development of HCC. Approach and Results We developed an HNF4 alpha target gene signature, which can accurately determine HNF4 alpha activity, and performed an exhaustive in silico analysis using hierarchical and K-means clustering, survival, and rank-order analysis of 30 independent data sets containing over 3500 individual samples. The association of changes in HNF4 alpha activity to CLD progression of various etiologies, including HCV- and HBV-induced liver cirrhosis (LC), NAFLD/NASH, and HCC, was determined. Results revealed a step-wise reduction in HNF4 alpha activity with each progressive stage of pathogenesis. Cluster analysis of LC gene expression data sets using the HNF4 alpha signature showed that loss of HNF4 alpha activity was associated with progression of Child-Pugh class, faster decompensation, incidence of HCC, and lower survival with and without HCC. A moderate decrease in HNF4 alpha activity was observed in NAFLD from normal liver, but a further significant decline was observed in patients from NAFLD to NASH. In HCC, loss of HNF4 alpha activity was associated with advanced disease, increased inflammatory changes, portal vein thrombosis, and substantially lower survival. Conclusions In conclusion, these data indicate that loss of HNF4 alpha function is a common event in the pathogenesis of CLDs leading to HCC and is important from both diagnostic and therapeutic standpoints.