HAF prevents hepatocyte apoptosis and progression to MASH and hepatocellular carcinoma through transcriptional regulation of the NF-κB pathway

• Published in: Hepatology (Baltimore, Md.)
• Main Authors: Acuña-Pilarte, Karen, Reichert, Ethan C, Song Green, Yangsook, Halberg, Lily M-T, Golkowski, Martin, Maguire, Kathleen M, Mimche, Patrice N, Kamdem, Severin Donald, Hu, Po-An, Wright, Jillian, Ducker, Gregory S, Voth, Warren P, O'Connell, Ryan M, McFarland, Sydney A, Egal, Erika Said Abu, Chaix, Amandine, Summers, Scott A, Reelitz, Jordan W, Maschek, J Alan, Cox, James E, Evason, Kimberley J, Koh, Mei Yee
• Format: Journal Article
• Language: English
• Published: United States 10.09.2024
• ISSN: 1527-3350

HCC incidence is increasing worldwide due to the obesity epidemic, which drives metabolic dysfunction-associated steatohepatitis (MASH) that can lead to HCC. However, the molecular pathways driving MASH-HCC are poorly understood. We have previously reported that male mice with haploinsufficiency of hypoxia-associated factor, HAF (SART1+/-) spontaneously develop MASH-HCC. However, the cell type(s) responsible for HCC associated with HAF loss are unclear. We generated SART1-floxed mice, which were crossed with mice expressing Cre-recombinase within hepatocytes (Alb-Cre; hepS-/-) or myeloid cells (LysM-Cre, macS-/-). HepS-/- mice (both male and female) developed HCC associated with profound inflammatory and lipid dysregulation suggesting that HAF protects against HCC primarily within hepatocytes. HAF-deficient hepatocytes showed decreased P-p65 and P-p50 and in many components of the NF-κB pathway, which was recapitulated using HAF siRNA in vitro. HAF depletion also triggered apoptosis, suggesting that HAF protects against HCC by suppressing hepatocyte apoptosis. We show that HAF regulates NF-κB activity by regulating transcription of TRADD and RIPK1. Mice fed a high-fat diet (HFD) showed marked suppression of HAF, P-p65 and TRADD within their livers after 26 weeks, but showed profound upregulation of these proteins after 40 weeks, implicating deregulation of the HAF-NF-κB axis in the progression to MASH. In humans, HAF was significantly decreased in livers with simple steatosis but significantly increased in HCC compared with normal liver. HAF is novel transcriptional regulator of the NF-κB pathway and is a key determinant of cell fate during progression to MASH and MASH-HCC.