Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1002629 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25535904_1.fastq.gz | Fastqsanger.gz | |||
| SRR25535904_2.fastq.gz | Fastqsanger.gz | |||
| SRR25535905_1.fastq.gz | Fastqsanger.gz | |||
| SRR25535905_2.fastq.gz | Fastqsanger.gz | |||
| SRR25535906_1.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:A Metabolic Switch Controlling Liver Cancer Evolution from Senescent NASH Hepatocytes
| PRJNA1107198 | ENA
Project description:A Metabolic Switch Controlling Liver Cancer Evolution from Senescent NASH Hepatocytes
| PRJNA1001982 | ENA
Project description:Hepatocellular carcinoma (HCC) originates from differentiated hepatocytes undergoing compensatory proliferation in livers damaged by viruses or nonalcoholic steatohepatitis (NASH). While increasing HCC risk, NASH triggers TP53-dependent hepatocyte senescence, which we found to parallel hypernutrition-induced DNA breaks. How this tumor-suppressive response is bypassed to license accumulation of oncogenic mutations and enable HCC progression was previously unknown. We identified the gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1) as a TP53 target that is elevated in senescent-like NASH hepatocytes but suppressed through promoter hypermethylation and proteasomal degradation in most human HCCs. FBP1 first declines in metabolically-stressed premalignant disease-associated hepatocytes and HCC progenitor cells, paralleling the protumorigenic activation of AKT and NRF2. By accelerating FBP1 and TP53 degradation AKT and NRF2 enhance the proliferation and metabolic activity of previously senescent HCC progenitors. The senescence-reversing NRF2-FBP1-AKT-TP53 metabolic switch, operative in mice and humans, also enhances proliferation-enabled accumulation of DNA damage-induced somatic mutations that drive NASH to HCC progression.
2025-01-10 | GSE266447 | GEO
Project description:Hepatocellular carcinoma (HCC), the third most common cancer, originates from differentiated hepatocytes undergoing compensatory proliferation in livers damaged primarily by viruses or nonalcoholic steatohepatitis (NASH)1,2. While increasing HCC risk3, NASH also induces TP53-dependent hepatocyte senescence4. How this tumor-suppressive response is activated but eventually bypassed to license HCC progression is unknown. We identified the gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1) as a TP53 target, induced in senescent NASH hepatocytes but downregulated in most human HCCs. Initial FBP1 downregulation in disease-associated hepatocytes, whose accumulation precedes HCC development5, activates AKT to inhibits GSK3 substrate binding, thereby augmenting activation of NRF2 which accelerates FBP1 and TP53 degradation. Intrinsic NRF2 activation and FBP1 loss trigger overlapping transcriptomic responses that suppress senescence, enhance hepatocyte proliferation and metabolism, and enable NRAS- or NASH-induced hepatocarcinogenesis. This AKT-dependent metabolic switch, operative in mice and humans, controls NASH to HCC progression. Our results further suggest that NASH-related hepatocyte senescence is triggered by hypernutrition-induced single strand DNA breaks. Senescence reversal enables HCC progenitor expansion and somatic mutagenesis.
2024-07-15 | GSE240047 | GEO
Project description:Background: Senescent hepatocytes accumulate in parallel with fibrosis progression during NASH. The mechanisms that enable progressive expansion of nonreplicating cell populations and the significance of that process in determining NASH outcomes are unclear. Many types of senescing cells upregulate the THBD-PAR-1 signaling axis to remain viable. Vorapaxar, an FDA-approved PAR-1 inhibitor, blocks the activity of that pathway. We used vorapaxar to determine if and how THBD-PAR1 signaling promotes fibrosis progression in NASH. Methods: We evaluated the THBD-PAR1 pathway in liver biopsies from NAFLD patient cohorts with a spectrum of liver fibrosis. Chow fed mice were treated with viral vectors to over-express p16 specifically in hepatocytes and induce replicative senescence. Effects on the THBD-PAR-1 axis and regenerative capacity were assessed; the transcriptome of p16 over-expressing hepatocytes was characterized and we examined how conditioned medium from senescent but viable (dubbed ‘undead’) hepatocytes reprograms hepatic stellate cells. A genetically obese mouse model of NASH with little liver fibrosis, and a diet-induced mouse model of NASH with advanced fibrosis were treated with vorapaxar to determine effects on hepatocyte senescence and liver damage. Results: Inducing senescence up-regulates the THBD-PAR1 signaling axis in hepatocytes and induces their expression of fibrogenic factors, including hedgehog ligands. Hepatocyte THBD-PAR1 signaling increases in NAFLD and supports sustained hepatocyte senescence that limits effective liver regeneration and promotes maladaptive repair. Inhibiting PAR-1 signaling with vorapaxar interrupts this process, reduces the burden of ‘undead’ senescent cells, and safely improves NASH and fibrosis despite ongoing lipotoxic stress Conclusion: The THBD-PAR1 signaling axis is a novel therapeutic target for NASH because blocking this pathway prevents accumulation of senescing but viable hepatocytes that generate factors that promote maladaptive liver repair.
2023-03-01 | GSE204901 | GEO
Project description:Current therapeutic strategies for treating non-alcoholic steatohepatitis (NASH) have failed to alleviate liver fibrosis, which is a devastating feature leading to hepatic dysfunction. Here, we integrated single-nucleus transcriptomics and epigenomics to characterize all major liver cell types during NASH development in mice and humans. The bifurcation of hepatocyte trajectory with NASH progression was conserved between mouse and human. At the non-alcoholic fatty liver (NAFL) stage, hepatocytes exhibited metabolic adaptation, whereas at the NASH stage, a subset of hepatocytes was enriched for the signatures of cell adhesion and migration, which was mainly demarcated by receptor tyrosine kinase EphB2. EphB2, acting as a downstream effector of Notch signaling in hepatocytes, was sufficient to induce cell-autonomously inflammation. Knockdown of Ephb2 in hepatocytes ameliorated inflammation and fibrosis in NASH. Thus, EphB2 expressing hepatocytes contribute to NASH progression and may serve as a potential therapeutic target.
2023-02-08 | GSE189600 | GEO
Project description:Macrophages are exquisitely capable of sensing danger-associated molecular patterns (DAMPs) and orchestrating inflammatory response during tissue injury. Nonalcoholic steatohepatitis (NASH) represents an advanced stage of metabolic fatty liver disease that increases the risk for cirrhosis and liver cancer. Pathogenic mechanisms of NASH center on hepatocyte injury and the ensuing immune response within the liver microenvironment. However, the nature of DAMPs released by injured hepatocytes and how they shape the liver immune milieu remain largely unknown. Here we show that lipid droplets (LDs) released by injured fatty hepatocytes provide a potent signal that triggers monocyte infiltration and maturation into Trem2+ macrophages, recently described as NASH-associated macrophages (NAMs) or lipid- associated macrophages. LD treatment exacerbated liver injury in mice with diet-induced NASH. We identified Membrane spanning 4-domains a7 (Ms4a7) as a NAM-specific pathogenic factor that was strongly induced in mouse and human NASH. Ms4a7 inactivation ameliorated key aspects of diet-induced NASH pathologies in mice. At the mechanistic level, Ms4a7 physically interacts with NLR family pyrin domain containing 3 (NLRP3) and is required for endosomal NLRP3 inflammasome activation. These findings illustrate a crucial role of Ms4a7 in driving pro-inflammatory signaling in NASH liver. Surprisingly, LD treatments attenuated Ms4a7 expression and NLRP3 inflammasome activation in cultured macrophages. As such, LDs serve as a DAMP signal that balances the induction of Trem2+ macrophages and NLRP3 inflammasome activation in NASH liver
2024-04-26 | GSE230700 | GEO
Project description:BACKGROUND & AIMS: Recent studies revealed that hemoglobin is expressed in some non-erythrocytes and it suppresses oxidative stress when overexpressed. Oxidative stress plays a critical role in the pathogenesis of non-alcoholic steatohepatitis (NASH). This study was to investigate whether hemoglobin is expressed in hepatocytes and how it is related to oxidative stress in NASH patients. METHODS: Microarray was performed to identify differentially expressed genes in NASH. Quantitative real time PCR (qRT-PCR) was used to examine gene expression levels. Western blotting and immunofluorescence staining were employed to examine hemoglobin proteins. Flow cytometry was used to measure intracellular oxidative stress. RESULTS: Analysis of microarray gene expression data has revealed a significant increase in the expression of hemoglobin alpha (HBA1) and beta (HBB) in liver biopspies from NASH patients. Increased hemoglobin expression in NASH was validated by qRT-PCR. However, the expression of erythrocyte specific marker genes such as SPTA, SPTB, GYPA, GATA1, and ALAS2 did not change, indicating that increased hemoglobin expression in NASH was not from erythropoiesis, but could result from increased expression in hepatocytes. Immunofluorescence staining demonstrated positive HBA1 and HBB expression in the hepatocytes of NASH livers. Hemoglobin expression was also observed in human hepatocellular carcinoma HepG2 cell line. Furthermore, treatment with hydrogen peroxide, a known oxidative stress inducer, induced a dose dependent increase in HBA1 expression in HepG2 cells. Intriguingly, forced hemoglobin expression suppressed oxidative stress. CONCLUSIONS: Oxidative stress upregulates hemoglobin expression in hepatocytes. Suppression of oxidative stress by hemoglobin could be a mechanism to protect hepatocytes from oxidative damage. These findings suggest that hemoglobin is an inducible antioxidant in hepatocytes in response to increased oxidative stress as found in NASH livers. Twelve biopsy diagnosed NASH patients were included in this study. For control groups, total RNA from 5 different subjects were purchased from ADMET. These subjects are free from liver disease.
2010-10-20 | E-GEOD-24807 | biostudies-arrayexpress
Project description:Non-alcoholic fatty liver disease is continuum of disorders among which non-alcoholic steatohepatitis (NASH) is particularly associated with a negative prognosis. Hepatocyte lipotoxicity is one of the main pathogenic factors of liver fibrosis and NASH. However, the molecular mechanisms regulating this process are poorly understood. Here, we integrated transcriptomic and chromatin accessibility analyses from human liver and mouse hepatocytes to identify lipotoxicity-sensitive transcription factors. We found that the transcription factors MAFK and TCF4 were activated in liver from NASH patients and by mouse hepatocyte lipotoxicity. Genetic deletion of these transcription factors protected hepatocytes against saturated fatty acid oversupply. Notably, MAFK- and TCF4-regulated gene expression linked to lipotoxicity closely correlated with transcriptional patters in fibrosis progression in NASH patients. Collectively, our findings uncovered novel molecular insights into lipotoxicityinduced NASH, revealing the relevance and therapeutic potential of MAFK and TCF4 in human disease.
2022-07-08 | PXD026717 | Pride
Project description:To study sex differences in the response to NASH in mice, single nucleus RNA sequencing of livers was performed. Single nucleus RNAseq demonstrated enrichment of differentially-expressed genes particularly in hepatocytes and stellate cells in females versus males fed FPC-NASH. Multiple regulons (transcription factors and target genes) implicated in lipid and other metabolic processes and hormone signaling (hepatocytes) and cell-cell communication and cell adhesion (stellate cells) were noted, which were enriched in female versus male FPC-NASH diet. Bulk liver RNAseq, RNAseq of isolated hepatocytes and hepatic stellate cells, and spatial transcriptomics, were analyzed as validation experiments.
2024-09-24 | GSE259410 | GEO