Potential utility of L-carnitine for preventing liver tumors derived from metabolic dysfunction-associated steatohepatitis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE261938 | GEO | 2024/04/24
REPOSITORIES: GEO
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Project description:Potential utility of L-carnitine for preventing liver tumors derived from metabolic dysfunction-associated steatohepatitis
| PRJNA1089610 | ENA
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: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
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
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
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: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
Project description:rs07-01_carnitine - carnitine effect - Effect of carnitine on the transcriptome of A. thaliana - Our objective is the description of the existence of an intracellular transport depend on the carnitine at Arabidopsis thaliana. For that, we planned the study of the response of the transcriptome in the presence of exogenic L-carnitine. Seedlings WT are cultivated on medium MS, 6 independent times. At 144h, the seedlings are collected and pools are formed with 3 samples. We proceed in the same way for the seedlings which are cultivated on medium MS containing L-carnitine 5mM. Keywords: treated vs untreated comparison
2008-03-05 | GSE10676 | GEO
Project description:Background: Biomarkers for metabolic dysfunction-associated steatohepatitis (MASH) have been considered based on proteomic and lipidomic data from plasma and liver tissue without clinical benefits. This study evaluated proteomics-based plasma and liver tissue biomarkers collected simultaneously from patients with metabolic dysfunction-associated steatotic liver disease (MASLD).
Methods: Liver tissue samples and plasma samples were collected during liver biopsy for diagnosis. Untargeted proteomics was performed on 64 patients with MASLD.
Results: Twenty plasma proteins were up or downregulated in patients with MASH compared with those without MASH. The biomarkers utilizing the best combinations of these plasma proteins had an area under the receiver operating curve (AUROC) of 0.671 for detecting those with MASH compared with those without it. However, none of the 20 plasma proteins were represented among the significantly regulated liver tissue proteins in patients with MASH. Ten of them displayed a trend and relevance in liver tissue with MASLD progression. These ten plasma proteins had an AUROC of 0.793 for MASH identification and higher positive and negative predictive values.
Conclusion: The plasma and liver protein expressions of patients with MASH were not directly comparable. Plasma protein biomarkers that are also expressed in liver tissue can help improve MASH detection.
2024-06-07 | MSV000094959 | MassIVE
Project description:Neutrophils, a major innate immune cell population, are the most abundant circulating white blood cell in humans. They play a crucial role in host defense against infection; however, aberrant neutrophil activation may induce tissue damage via sterile inflammation. Neutrophil accumulation has been identified as a feature of the inflammatory response observed MASH and has been associated with liver fibrosis and cirrhosis. In the present study, we used RNA-Seq analysis of purified neutrophils to characterize their dysregulation in MASH.
2024-05-15 | GSE247467 | GEO