Proteomics

Dataset Information

0

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


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-kB 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-kB 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-kB 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-kB pathway and is a key determinant of cell fate during progression to MASH and MASH-HCC.

INSTRUMENT(S): timsTOF Pro 2

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Mei Yeh Koh  

PROVIDER: MSV000095959 | MassIVE |

REPOSITORIES: MassIVE

Dataset's files

Source:
Action DRS
Other
Items per page:
1 - 1 of 1

Similar Datasets

2024-06-05 | GSE261057 | GEO
2016-12-31 | GSE67676 | GEO
2024-10-01 | GSE273523 | GEO
2010-08-01 | GSE17609 | GEO
2023-07-03 | GSE166875 | GEO
2020-09-25 | GSE158479 | GEO
2012-01-24 | E-GEOD-33322 | biostudies-arrayexpress
2024-10-17 | GSE272024 | GEO
2024-08-07 | GSE265985 | GEO
2020-03-22 | GSE139251 | GEO