Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1225187 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32381400_1.fastq.gz | Fastqsanger.gz | |||
| SRR32381400_2.fastq.gz | Fastqsanger.gz | |||
| SRR32381401_1.fastq.gz | Fastqsanger.gz | |||
| SRR32381401_2.fastq.gz | Fastqsanger.gz | |||
| SRR32381402_1.fastq.gz | Fastqsanger.gz |
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Project description:Metabolic Dysfunction Associated Steatohepatitis (MASH) is characterized by excess circulating toxic lipids, hepatic steatosis, and liver inflammation. Monocyte adhesion to the liver sinusoidal endothelial cells (LSEC) and transendothelial migration (TEM) are crucial in the inflammatory process. LSEC under lipotoxic stress develops a pro-inflammatory phenotype known as endotheliopathy. However, the mediators of endotheliopathy remain obscure. Primary mouse LSEC isolated from C57BL/6J mice on chow or MASH-inducing diets rich in fat, fructose, and cholesterol (FFC) were subjected to multi-omics profiling. Mice with established MASH, due to a choline-deficient high-fat diet (CDHFD) or FFC diet, were treated with two structurally distinct GSK3 inhibitors [LY2090314, elraglusib (9-ING-41)]. Integrated pathway analysis of mouse LSEC proteome and transcriptome indicates that leukocyte TEM and focal adhesion are major pathways altered in MASH. Kinome profiling of the LSEC phospho-proteome identified GSK3β as the major kinase hub in MASH. GSK3β activating phosphorylation was increased in primary human LSEC treated with the toxic lipid palmitate and in human MASH. Palmitate upregulated the expression of C-X-C motif chemokine ligand 2, intracellular adhesion molecule 1, and phosphorylated focal adhesion kinase, via a GSK3-dependant mechanism. Congruently, the adhesive and transendothelial migratory capacities of primary human neutrophils and THP-1 monocytes through LSEC monolayer under lipotoxic stress were reduced by GSK3 inhibition. Treatment with the GSK3 inhibitors LY2090314 and elraglusib ameliorated liver inflammation, injury, and fibrosis in FFC and CDHFD-fed mice, respectively. Immunophenotyping of intrahepatic leukocytes from CDHFD-fed mice treated with elraglusib using cytometry by the time of flight showed reduced proinflammatory monocyte-derived macrophages and monocyte-derived dendritic cells infiltration.GSK3 inhibition attenuates lipotoxicity-induced LSEC endotheliopathy and may serve as a potential therapeutic strategy in human MASH.
2024-06-22 | PXD048073 | Pride
Project description:To determine the effect of SphK2 KO on liver inflammation in an early MASH mouse model To determine the effect of WDSW on liver inflammation in an early MASH mouse model
2024-11-20 | GSE280083 | GEO
Project description:Background & Aims: Fibrosis drives liver-related mortality in metabolic dysfunction-associated steatohepatitis (MASH), yet we have limited medical therapies to target MASH-fibrosis progression. Here we report that mannose, a simple sugar, attenuates MASH steatosis and fibrosis in two robust murine models and human liver slices. Methods: The well-validated FAT-MASH murine model for liver steatosis and fibrosis was employed. Mannose was supplied in the drinking water at the start (“Prevention” group) or at week 6 of the 12-week MASH regimen (“Therapy” group). The in vivo anti-fibrotic effects of mannose supplementation were tested in a second model of carbon tetrachloride (CCl4)-induced liver fibrosis. A quantitative and automated digital pathology approach was used to comprehensively assess steatosis and fibrosis phenotypes. Mannose was also tested in vitro in human and primary mouse hepatocytes conditioned with free fatty acids alone or with fructose, and Human Precision Cut Liver Slices (hPCLS) from patients with end-stage MASH cirrhosis. Results: Oral mannose supplementation improved liver fibrosis in vivo in both FAT-MASH and CCl4 mouse models, as well as in hPCLS MASH samples. Mannose also reduced liver steatosis in FAT-MASH mice, and in human and mouse hepatocytes in vitro. Ketohexokinase (KHK), the main enzyme in fructolysis, was decreased with mannose in whole mouse liver, cultured hepatocytes, and hPCLS. Removal of fructose or overexpression of KHK each abrogated the anti-steatotic effects of mannose. Conclusions: This study identifies mannose as a novel therapeutic candidate for MASH that mitigates steatosis by dampening hepatocyte KHK expression and exerts independent anti-fibrotic effects in two mouse models and human liver tissue slices.
2025-01-31 | GSE287943 | GEO
Project description:To determine the effect of SphK2 KO on liver metabolic-associated gene expression in an early MASH mouse model To determine the effect of WDSW on liver metabolic-associated gene expression in an early MASH mouse model
2024-11-20 | GSE280101 | GEO
Project description:Metabolic dysfunction-associated steatoheptaitis (MASH) is a chronic liver disease caused by prolonged poor diet. During MASH-induced chirrosis in humans and diet-induced MASH in murine models, T cells accumulated in the liver but their function in MASH is unresolved. We aimed to evaluated differences in T cell phenotype and T cell receptor (TCR) repertoire in T cells from the livers of diseased humans and murine models. This set contains mouse sequencing data.
2025-01-22 | GSE270490 | GEO
Project description:We explore whether a low-energy diet intervention for Metabolic dysfunction-associated steatohepatitis (MASH) improves liver disease by means of modulating the gut microbiome. 16 individuals were given a low-energy diet (880 kcal, consisting of bars, soups, and shakes) for 12 weeks, followed by a stepped re-introduction to whole for an additional 12 weeks. Stool samples were obtained at 0, 12, and 24 weeks for microbiome analysis. Fecal microbiome were measured using 16S rRNA gene sequencing. Positive control (Zymo DNA standard D6305) and negative control (PBS extraction) were included in the sequencing. We found that low-energy diet improved MASH disease without lasting alterations to the gut microbiome.
2024-12-31 | E-MTAB-14061 | biostudies-arrayexpress
Project description:Background & Aims Obesity is a major risk factor for metabolic associated steatotic liver disease (MASLD) which can progress from metabolic associated steatotic liver (MASL) to metabolic associated steatohepatitis (MASH). There are currently no effective and validated screening tools to stratify obese patients with a greater risk for MASH, independent of liver fibrosis, at a population level. We aimed to characterise the highly abundant and small protein plasma proteomes of worsening MASLD and overlay the liver-secreted proteome to generate a predictive model to stratify patients with and without MASH. Methods Venous blood and liver wedge biopsies were taken from 160 patients undergoing bariatric surgery. MASLD severity was assessed histologically. Liver biopsies from a subset of 96 patients were precision-cut and cultured to assess liver-secreted proteins. Proteomic analysis was performed using liquid chromatography-tandem mass spectrometry on the plasma and the incubation medium cutoff the liver slices. Results Current non-invasive scores failed to stratify MASH in our cohort. The top200 plasma proteome exhibited mild changes in patients with MASH compared to those with No pathology, while the SPEA approach identified substantial differences in plasma proteins of patients with MASH compared to those without MASH. Liver-secreted proteins were remodelled in MASH compared to MASL and individuals with No pathology. There were no significant changes in the liver-secreted proteins and plasma proteome when comparing MASL to those with No pathology. The APASHA model, comprised of APOF, PCSK9, AFM, and S100A6, HbA1c % and AZGP1 stratified MASH in the discovery (AUROC: 0.887, p<0.0001) and validation cohorts (AUROC:0.7673, p=0.0002) and outcompeted other non-invasive scores. Conclusions These proteomic investigations provide a detailed description of liver-secreted and plasma proteome with worsening MASLD. MASH remodels plasma and liver-secreted proteins. Plasma proteomics generated the APASHA model validated in two Australian bariatric cohorts. Further investigation is warranted to interrogate the utility of the APASHA model as a non-invasive risk prediction model in additional cohorts. Lay Summary: Metabolic-associated steatohepatitis (MASH), a more advanced form of metabolic-associated steatotic liver disease (MASLD), alters the levels of many proteins secreted by the liver and in the blood and those. The APASHA model, which is based on proteins that change in the blood or are secreted by the liver in cases of MASH, could potentially be developed into a simple blood test to predict MASH in high-risk groups.
2025-04-14 | PXD052784 | Pride
Project description:Background & Aims: Chronic HBV patients with concomitant metabolic dysfunction-associated steatohepatitis (MASH) have been shown to develop more advanced fibrosis faster with more severe liver disease as compared to patients with chronic HBV alone. However, our understanding of the underlying mechanisms is limited. Here we study how MASH co-morbidity impact immune activity in the liver of patients with chronic HBV infection. Methods: Bulk RNA sequencing was performed on liver biopsies from patients with only MASH (n=10), only HBeAg-negative chronic HBV (ENEG; n=11), combined MASH/ENEG (n=9) and healthy controls (n=9). Biopsies with no or minimal fibrosis (≤F2) were selected to avoid confounding effects of fibrosis. We compared whole transcriptome data from patients with MASH/ENEG to those with ENEG alone to determine the impact of MASH co-morbidity on chronic hepatitis B. Results: There is a high degree of overlap of liver gene expression profiles in patients with only ENEG versus those with only MASH compared to healthy controls, suggesting a largely shared mechanism of liver dysfunction and immune activity for these distinct conditions. In patients with ENEG, MASH co-morbidity significantly reduced interferon pathway activity (NES=2.03, p.adj=0.0251), the expression of ISGs (e.g., IFIT2, IFI27, IFITM1, IFI6), and macrophage gene signatures (e.g., MARCO, CD163, CD5L, CD63), when compared to patients with ENEG alone. Conclusions: Transcriptomic profiling of the liver suggests that MASH negatively impacts ISGs expression in the liver of patients with ENEG, which may affect antiviral immune pathways, viral replication and inflammatory responses resulting in an increased risk of advanced fibrosis in patients with chronic hepatitis B. Our study provides valuable insights for guiding future research aimed at developing effective, tailored strategies for managing patients with both conditions.
2024-10-31 | GSE274114 | GEO
Project description:Background & Aims Obesity is a major risk factor for metabolic associated steatotic liver disease (MASLD) which can progress from metabolic associated steatotic liver (MASL) to metabolic associated steatohepatitis (MASH). There are currently no effective and validated screening tools to stratify obese patients with a greater risk for MASH, independent of liver fibrosis, at a population level. We aimed to characterise the highly abundant and small protein plasma proteomes of worsening MASLD and overlay the liver-secreted proteome to generate a predictive model to stratify patients with and without MASH. Methods Venous blood and liver wedge biopsies were taken from 160 patients undergoing bariatric surgery. MASLD severity was assessed histologically. Liver biopsies from a subset of 96 patients were precision-cut and cultured to assess liver-secreted proteins. Proteomic analysis was performed using liquid chromatography-tandem mass spectrometry on the plasma and the incubation medium cutoff the liver slices. Results Current non-invasive scores failed to stratify MASH in our cohort. The top200 plasma proteome exhibited mild changes in patients with MASH compared to those with No pathology, while the SPEA approach identified substantial differences in plasma proteins of patients with MASH compared to those without MASH. Liver-secreted proteins were remodelled in MASH compared to MASL and individuals with No pathology. There were no significant changes in the liver-secreted proteins and plasma proteome when comparing MASL to those with No pathology. The APASHA model, comprised of APOF, PCSK9, AFM, and S100A6, HbA1c % and AZGP1 stratified MASH in the discovery (AUROC: 0.887, p<0.0001) and validation cohorts (AUROC:0.7673, p=0.0002) and outcompeted other non-invasive scores. Conclusions These proteomic investigations provide a detailed description of liver-secreted and plasma proteome with worsening MASLD. MASH remodels plasma and liver-secreted proteins. Plasma proteomics generated the APASHA model validated in two Australian bariatric cohorts. Further investigation is warranted to interrogate the utility of the APASHA model as a non-invasive risk prediction model in additional cohorts.
2025-04-14 | PXD052798 | Pride
Project description:Background & Aims: Kupffer cell (KC) participates in hepatic inflammation and fibrosis in metabolic dysfunction-associated steatohepatitis (MASH), but underlying molecular mechanisms are not fully resolved. Transcription factor CCAAT/enhancer binding protein β (C/EBPβ) has been implicated in both metabolic and immune dysregulations. In this study, we aimed to investigate the role of C/EBPβ in KCs under the context of MASH pathogenesis. Approach & Results: A 12-week high-fat and high-cholesterol diet (HFHCD) model was used in wild-type or KC-specific Cebpb heterozygous knockout mice (Cebpbfl/+;Clec4f-iCre), followed by evaluation of liver using histopathology, analytical flow cytometry and RNA-seq. We found that HFHCD in wild-type mice induced significant inflammatory immune cell infiltration, including increased proportion of monocyte-derived macrophages (MoMFs), accompanied with concomitant increase in C/EBPβ protein level in KCs. KC-specific Cebpb heterozygous knockout significantly reduced HFHCD-induced immune cell (including MoMFs, neutrophils and CD8+ T cells) infiltration and inflammation-related gene expression in liver. FACS-sorted KCs of HFHCD-treated mice were used for C/EBPβ CUT&Tag-seq. We found that C/EBPβ activity was increased in MASH KCs, leading to selective promotion on part of MASH-induced genes. Combined analysis of RNA-seq and CUT&Tag-seq, along with dual luciferase reporter assay identified Vcam1 (encoding vascular cell adhesion molecule 1, VCAM1) as a key downstream gene of C/EBPβ in KCs of murine MASH liver. In both murine liver and MASH patients, VCAM1 was predominantly expressed in KCs. Its expression in liver was significantly increased after MASH onset, and it was involved in promoting immune cell infiltration in MASH. Conclusions: In MASH pathogenesis, increased C/EBPβ in KCs act as a MASH-associated stimulus-regulated TF, and has a direct transcriptional activation effect on Vcam1 promoter, leading to abnormal elevation in VCAM1 expression in KCs and subsequent immune cell infiltration. Our findings suggest that C/EBPβ in KCs can be a potential therapeutic target for NASH inflammation.
2025-07-23 | GSE273162 | GEO