The role of the HNF4alpha transcription network in the maintenance of key hepatocyte functions during acute liver failure

• Applicant: Dr. Honglei Weng, Ph.D.
• Subject Area: Gastroenterology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 515099327

Massive hepatocyte loss results in acute liver failure (ALF), a medical emergency with high mortality worldwide. In such a detrimental condition, performance of essential liver functions by the remaining hepatocytes and activated liver progenitor cells (LPC) is crucial for the survival of patients. As a master hepatic transcription factor, HNF4alpha expression in the remaining hepatocytes and LPC is essential to maintain key liver functions in ALF. To date, the detailed mechanism regulating HNF4alpha under severe disease conditions, such as massive hepatocyte loss and severe inflammation, remains largely unknown. Our recent studies showed that activin induces coagulation factor expression by upregulating HNF4alpha expression in LPC, and thus determines the clinical outcome of ALF. In addition, the binding of HNF4alpha to target genes’ enhancers requires pioneer factor FOXA2 to keep chromatin accessible in both hepatocytes and LPC. Based on these new insights, we propose to investigate the following hypotheses: (1) Supported by pioneer factor FOXA2, HNF4 synergizes with additional transcription factors such as C/EBPalpha to form a transcriptional network in hepatocytes that regulates key functional genes for physiological demand. (2) When severe inflammation inhibits HNF4alpha expression in hepatocytes, FOXA2 coordinates with transcription factors such as RAR to regulate key functional genes. (3) In ALF with MHN, supported by FOXA2 activated LPC initiate an HNF4-dominated transcriptional network to take over key hepatocyte functions in areas in the absence of hepatocytes. To confirm these hypotheses, primary hepatocytes and LPC as well as cell lines will be used for molecular biological investigation in vitro. The role and potential mechanisms of transcription factors in ALF will be examined in vivo in ALF patients, acetaminophen- and LPS combined with D-galactosamine-treated mice and metronidazole-treated zebrafish. Clarification of the exact molecular mechanisms maintaining essential liver functions following massive hepatocyte loss will enhance our understanding of ALF and provide novel targets for therapeutic intervention.

• DFG Programme: Research Grants