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DNA methylation analysis of liver samples from healthy individuals and patients with advanced metabolic dysfunction associated steatohepatitis (MASH)

ABSTRACT: DNA methylation analysis of liver samples from healthy individuals and patients with advanced metabolic dysfunction associated steatohepatitis (MASH)

PROVIDER: PRJNA1007758 | ENA |

REPOSITORIES: ENA

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DNA methylation analysis of liver samples from healthy individuals and patients with advanced metabolic dysfunction associated steatohepatitis (MASH)

Project description:To investigate MASH-associated changes in DNA-methylation, a genome-wide DNA methylation profiling of livers from healthy individuals compared to those with MASH was performed using the 850K MethylationEPIC BeadChip Array. Further differential methylation analysis allowed us to identify a MASH epigenetic signature. Both males and females were included in this cohort, consisting of 4 MASH patients and 3 healthy individuals.

2024-03-01 | GSE241366 | GEO

Serum Protein Risk Stratification Score for Diagnostic Evaluation of Metabolic Dysfunction-Associated Steatohepatitis (MASH)

Project description:Reliable non-invasive tools to diagnose at risk metabolic dysfunction-associated steatohepatitis (MASH) are urgently needed to improve management. We developed a risk stratification score incorporating proteomics-derived serum markers with clinical variables to identify high risk MASH patients (NAFLD Activity Score (NAS) >4 and fibrosis score >2). In this three-phase proteomic study of biopsy-proven metabolic dysfunction-associated steatotic fatty liver disease (MASLD), we first developed a multi-protein predictor for discriminating NAS>4 based on SOMAscan proteomics quantifying 1,305 serum proteins from 57 US patients. Four key predictor proteins were verified by ELISA in the expanded US cohort (N=168), and enhanced by adding clinical variables to create the 9-feature MASH Dx Score which predicted MASH and also high risk MASH (F2+). The MASH Dx Score was validated in two independent, external cohorts from Germany (N=139) and Brazil (N=177). The discovery phase identified a 6-protein classifier that achieved an AUC of 0.93 for identifying MASH. Significant elevation of four proteins (THBS2, GDF15, SELE, IGFBP7) was verified by ELISA in the expanded discovery and independently in the two external cohorts. MASH Dx Score incorporated these proteins with established MASH risk factors (age, BMI, ALT, diabetes, hypertension) to achieve good discrimination between MASH and MASLD without MASH (AUC:0.87- discovery; 0.83- pooled external validation cohorts), with similar performance when evaluating high risk MASH F2-4 (vs. MASH F0-1 and MASLD without MASH). The MASH Dx Score offers the first reliable non-invasive approach combining novel, biologically plausible ELISA-based fibrosis markers and clinical parameters to detect high risk MASH in patient cohorts from the US, Brasil and Europe.

2023-12-22 | GSE251855 | GEO

Changes in intestinal permeability and gut microbiota following diet-induced weight loss in patients with metabolic dysfunction-associated steatohepatitis and liver fibrosis

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

Potential utility of L-carnitine for preventing liver tumors derived from metabolic dysfunction-associated steatohepatitis

Project description:We examined the potential utility of L-carnitine for alleviating metabolic dysfunction-associated steatohepatitis (MASH) and preventing the development of hepatocellular carcinoma. Short-term L-carnitine administration ameliorated MASH through its anti-inflammatory effects.

2024-04-24 | GSE261938 | GEO

Metabolic dysfunction-associated steatohepatitis reduces interferon and macrophage liver gene signatures in chronic HBV patients

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

Establishment and Characterization of Mouse Metabolic dysfunction-associated steatohepatitis-related Hepatocellular carcinoma organoids

Project description:Metabolic dysfunction-associated steatohepatitis is a form of chronic liver inflammation associated with metabolic syndrome, such as obesity and a major cause of hepatocellular carcinoma. Multi-biotics, a soymilk fermented with lactic acid bacteria, are known to alleviate obesity by lowering lipid profile. In this study, we investigated efficacy of multi-biotics in MASH-related HCC using mouse model fed choline-deficient L-amino acid-defined high-fat diet, and determined that tumor regression was not affected by multi-biotics. We established mouse MASH-related HCC organoids, and performed RNA-sequencing to identify transcriptomic features in MASH-HCC treated multi-biotics. We also examined response of MASH-related HCC to four HCC treatment drugs, and MASH-related HCC treated multi-biotics was good response to Lenvatinib. We established Lenvatinib-resistant MASH-related HCC organoids by administrating repeatedly Lenvatinib, and identified enriched pathways in Lenvatinib-resistant models. This study provides a tool for studying MASH-related HCC treatment and Lenvatinib resistance by establishing the MASH-related HCC and Lenvatinib resistance organoid model.

2024-10-17 | GSE272024 | GEO

Serum Protein Risk Stratification Score for Diagnostic Evaluation of Metabolic Dysfunction-Associated Steatohepatitis (MASH)

Project description:Serum Protein Risk Stratification Score for Diagnostic Evaluation of Metabolic Dysfunction-Associated Steatohepatitis (MASH)

| PRJNA1055558 | ENA

Cholesterol-Associated Locus EHBP1 Protects Against MASH Fibrosis

Project description:Excess cholesterol accumulation contributes to fibrogenesis in metabolic dysfunction-associated steatohepatitis (MASH, formerly known as nonalcoholic steatohepatitis [NASH]), but how hepatic cholesterol metabolism becomes dysregulated in MASH is not completely understood. We show here that human fibrotic MASH livers have decreased EHBP1, a novel GWAS locus associated with LDL cholesterol, and that the EHBP1 rs10496099 T>C variant in MASH patients is associated with decreased hepatic EHBP1 expression and with augmented MASH fibrosis. Congruent with the human data, EHBP1 loss- and gain-of-function increases and decreases MASH fibrosis in mice, respectively. Mechanistic studies reveal that EHBP1 promotes sortilin (SORT1)-mediated PCSK9 secretion, leading to LDLR degradation, decreased LDL uptake, and reduced TAZ, a fibrogenic effector. At a cellular level, EHBP1 deficiency affects intracellular localization of retromer, a protein complex required for sortilin stabilization. Our novel therapeutic approach to stabilizing retromer is effective in mitigating MASH fibrosis. Moreover, we show that the TNFα/PPARα pathway suppresses EHBP1 in MASH. These data not only provide new mechanistic insight into the role of EHBP1 in cholesterol metabolism and MASH fibrosis by uncovering the interaction between EHBP1 and other cholesterol-related loci, including SORT1, PCSK9, and LDLR, but also elucidate a novel interplay between inflammation and EHBP1-mediated cholesterol metabolism.

2025-01-23 | GSE232780 | GEO

Genetic and pharmacological targeting of hepatic oxalate overproduction ameliorates metabolic dysfunction-associated steatohepatitis

Project description:Metabolic dysfunction-associated steatohepatitis (MASH) is on the rise, and with limited pharmacological therapy available, identification of new metabolic targets is urgently needed. Oxalate is a terminal metabolite produced from glyoxylate by lactate dehydrogenase (LDHA). The liver-specific alanine-glyoxylate aminotransferase (AGXT) detoxifies glyoxylate, preventing oxalate accumulation. We report that AGXT is suppressed and LDHA is activated in livers from patients and mice with MASH, leading to oxalate overproduction. In turn, oxalate promotes steatosis in hepatocytes by inhibiting peroxisome proliferator activated receptor-alpha (PPARα) transcription and fatty acid β-oxidation (FAO), and induces monocyte chemotaxis via C-C motif chemokine ligand 2. In male mice with diet-induced MASH, blocking oxalate overproduction through hepatocyte-specific AGXT overexpression or pharmacological inhibition of LDHA potently lower steatosis, inflammation, and fibrosis by inducing PPARα-driven FAO, and suppressing monocyte chemotaxis, nuclear factor-kappaB and transforming growth factor-beta targets. These findings highlight hepatic oxalate overproduction as a new target for the treatment of MASH.

2024-08-07 | GSE265985 | GEO

Transcriptomic characterization of circulating neutrophils isolated from patients with metabolic dysfunction-associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis (NASH).

Project description:Transcriptomic characterization of circulating neutrophils isolated from patients with metabolic dysfunction-associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis (NASH).

| PRJNA1038739 | ENA

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