Karen Acuña-Pilarte, Ethan C. Reichert, Yangsook Song Green, Lily M-T. Halberg, Martin Golkowski, Kathleen M. Maguire, Patrice N. Mimche, Severin Donald Kamdem, Po-An Hu, Jillian Wright, Gregory S. Ducker, Warren P. Voth, Ryan M. O’Connell, Sydney A. McFarland, Erika Said Abu Egal, Amandine Chaix, Scott. A. Summers, Jordan W. Reelitz, J. Alan Maschek, James E. Cox, Kimberley J. Evason, Mei Yee Koh
{"title":"HAF prevents hepatocyte apoptosis and progression to MASH and hepatocellular carcinoma through transcriptional regulation of the NF-κB pathway","authors":"Karen Acuña-Pilarte, Ethan C. Reichert, Yangsook Song Green, Lily M-T. Halberg, Martin Golkowski, Kathleen M. Maguire, Patrice N. Mimche, Severin Donald Kamdem, Po-An Hu, Jillian Wright, Gregory S. Ducker, Warren P. Voth, Ryan M. O’Connell, Sydney A. McFarland, Erika Said Abu Egal, Amandine Chaix, Scott. A. Summers, Jordan W. Reelitz, J. Alan Maschek, James E. Cox, Kimberley J. Evason, Mei Yee Koh","doi":"10.1097/hep.0000000000001070","DOIUrl":null,"url":null,"abstract":"Background: 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 (<jats:italic toggle=\"yes\">SART1</jats:italic> <jats:sup> +/-</jats:sup>) spontaneously develop MASH-HCC. However, the cell type(s) responsible for HCC associated with HAF loss are unclear. Results: We generated <jats:italic toggle=\"yes\">SART1</jats:italic>-floxed mice, which were crossed with mice expressing Cre-recombinase within hepatocytes (Alb-Cre; hepS<jats:sup>-/-</jats:sup>) or myeloid cells (LysM-Cre, macS<jats:sup>-/-</jats:sup>). <jats:italic toggle=\"yes\">HepS</jats:italic> <jats:sup> -/-</jats:sup> 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 <jats:italic toggle=\"yes\">in vitro</jats:italic>. 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 <jats:italic toggle=\"yes\">TRADD</jats:italic> and <jats:italic toggle=\"yes\">RIPK1</jats:italic>. 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. Conclusions: 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.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":12.9000,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Hepatology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1097/hep.0000000000001070","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GASTROENTEROLOGY & HEPATOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background: 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. Results: 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. Conclusions: 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.
期刊介绍:
HEPATOLOGY is recognized as the leading publication in the field of liver disease. It features original, peer-reviewed articles covering various aspects of liver structure, function, and disease. The journal's distinguished Editorial Board carefully selects the best articles each month, focusing on topics including immunology, chronic hepatitis, viral hepatitis, cirrhosis, genetic and metabolic liver diseases, liver cancer, and drug metabolism.