Pioneer factor FOXA2 is essential for maintaining the urea cycle in acute liver failure

Background and Aims Disruption of the urea cycle results in hyperammonemia and thus causes hepatic encephalopathy (HE), a lethal complication of acute liver failure (ALF). A complete urea cycle requires six enzymes, including the rate-limiting enzyme carbamoyl phosphate synthetase I (CPS1). To date, the detailed regulation of CPS1 transcription in order to maintain urea cycle in ALF remains largely unknown.

Methods Expression of CPS1 and transcription factors such as FOXA2 and C/EBPα was examined by immunohistochemistry in liver tissues collected from 78 ALF patients including 27 with HE. The regulatory mechanisms of these factors on CPS1 and OTC transcription were investigated in vitro. The effect of FOXA2 in ALF was further investigated in acetaminophen-treated mice with or without adeno-associated virus serotype 8 (AAV8)-Foxa2 injection.

Results Physiologically, CPS1 transcription requires FOXA2 to maintain chromatin accessibility on their enhancers, which provides open binding sites for C/EBPα. In ALF, hepatic C/EBPα expression is inhibited by inflammation. In this setting, retinoic acid receptor synergizes with FOXA2 to maintain CPS1 transcription. Once ALF patients suffer from massive hepatic necrosis, liver progenitor cells perform the urea cycle to prevent hyperammonemia by initiating a transcription network comprising FOXA2 and C/EBPα. In ALF, HE occurs in patients lacking expression of these transcription factors. In mice with acetaminophen-induced ALF, injection of Foxa2-AAV8 maintains urea cycle and prevents hyperammonemia.

Conclusions FOXA2 is essential for maintaining the urea cycle. Pharmaceutical induction of hepatic FOXA2 expression might represent a novel approach to treat HE in ALF.

Publication History

Article published online:
18 January 2023