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A Mouse Model for Metabolic Dysfunction-associated Steatotic Liver Disease and Hepatocellular Carcinoma [ATAC-seq]

ABSTRACT: A Mouse Model for Metabolic Dysfunction-associated Steatotic Liver Disease and Hepatocellular Carcinoma [ATAC-seq]

PROVIDER: PRJNA1032056 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26515782_1.fastq.gz	Fastqsanger.gz
	SRR26515782_2.fastq.gz	Fastqsanger.gz
	SRR26515783_1.fastq.gz	Fastqsanger.gz
	SRR26515783_2.fastq.gz	Fastqsanger.gz
	SRR26515784_1.fastq.gz	Fastqsanger.gz

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A Mouse Model for Metabolic Dysfunction-associated Steatotic Liver Disease and Hepatocellular Carcinoma

Project description:A Mouse Model for Metabolic Dysfunction-associated Steatotic Liver Disease and Hepatocellular Carcinoma

| PRJNA1032073 | ENA

A Mouse Model for Metabolic Dysfunction-associated Steatotic Liver Disease and Hepatocellular Carcinoma [RNA-seq]

Project description:The lack of an appropriate preclinical model of metabolic dysfunction-associated steatotic liver disease (MASLD) that recapitulates the whole disease spectrum impedes exploration of disease pathophysiology and the development of effective treatment strategies. Considering the fact that MASLD patients accompanying type 2 diabetes mellitus (T2DM) have high risk of developing metabolic dysfunction-associated steatohepatitis (MASH), advanced fibrosis, and HCC, we treated low-dose streptozotocin (STZ; 40 mg/kg) for 5 consecutive days and subsequently fed a high-fat diet (HFD) to male C57BL/6J mice at 7 weeks of age (STZ+HFD). STZ+HFD mice gradually developed fatty liver, MASH, hepatic fibrosis, and hepatocellular carcinoma (HCC) in the context of metabolic dysfunction. In particular, from 20 weeks of age, MASH was evident, and from 32 weeks of age, advanced fibrosis was developed. At 38 weeks, a proportion of STZ+HFD mice developed HCC, which was subsequently observed in all mice up to 68 weeks of age. Furthermore, the hepatic transcriptomic features of STZ+HFD mice closely reflected those of obese patients with T2DM, MASH and MASLD-related HCC. Notably, dietary changes and tirzepatide administration alleviated MASH, hepatic fibrosis, and hepatic tumorigenesis in STZ+HFD mice. In conclusion, a murine model recapitulating the main histopathologic, transcriptomic, and metabolic alterations observed in MASLD patients with metabolic dysfunction was successfully established.

2024-06-17 | GSE246221 | GEO

A Mouse Model for Metabolic Dysfunction-associated Steatotic Liver Disease and Hepatocellular Carcinoma [RNA-seq]

Project description:A Mouse Model for Metabolic Dysfunction-associated Steatotic Liver Disease and Hepatocellular Carcinoma [RNA-seq]

| PRJNA1032104 | ENA

A Mouse Model for Metabolic Dysfunction-associated Steatotic Liver Disease and Hepatocellular Carcinoma [ATAC-seq]

Project description:The lack of an appropriate preclinical model of non-alcoholic fatty liver disease (NAFLD) that recapitulates the whole disease spectrum impedes exploration of disease pathophysiology and the development of effective treatment strategies. Therefore, we developed new mose model with Streptozotocin (STZ)and high-fat diet (HFD). In breif, male C57BL/6J mice were injected with low-dose streptozotocin (40 mg/kg) for 5 consecutive days beginning at 7 weeks of age and subsequently fed a high-fat diet from week 8 (STZ+HFD) onwards. Hepatic histopathology, transcriptomics, epigenetics, and metabolic phenotypes were evaluated at various time-points. The hepatic transcriptomes of STZ+HFD mice and NAFLD patients with similar liver histopathology were compared. In STZ+HFD mice, dietary changes from HFD to standard chow and administration of tirzepatide, a dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist, were introduced to assess the therapeutic efficacy of these interventions. STZ+HFD mice gradually developed fatty liver, non-alcoholic steatohepatitis (NASH), hepatic fibrosis, and hepatocellular carcinoma (HCC) in the context of metabolic dysfunction. In particular, from 32 weeks of age, NASH and advanced fibrosis were evident. At 38 weeks, a proportion of STZ+HFD mice developed HCC, which was subsequently observed in all mice up to 68 weeks of age. Furthermore, the hepatic transcriptomic features of STZ+HFD mice closely reflected those of patients with NASH and NAFLD-related HCC. Notably, dietary changes and tirzepatide administration alleviated NASH, hepatic fibrosis, and hepatic tumorigenesis in STZ+HFD mice. Put together, we established a murine model recapitulating the main histopathologic, transcriptomic, and metabolic alterations observed in NAFLD patients with metabolic dysfunction was successfully established.

2024-06-17 | GSE246213 | GEO

Aging Promotes Metabolic Dysfunction-Associated Steatotic Liver Disease by Inducing Ferroptotic Stress

Project description:Aging Promotes Metabolic Dysfunction-Associated Steatotic Liver Disease by Inducing Ferroptotic Stress

| PRJNA1094958 | ENA

Aging Promotes Metabolic Dysfunction-associated Steatotic Liver Disease and Multi-Organ Dysfunction by Inducing Ferroptotic Stress

Project description:Aging Promotes Metabolic Dysfunction-associated Steatotic Liver Disease and Multi-Organ Dysfunction by Inducing Ferroptotic Stress

| PRJNA1091908 | ENA

Binding of the spike of SARS-CoV-2 to steatotic hepatocytes promotes metabolic dysfunction

Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a multi-organ damage that includes hepatic dysfunction, which has been observed in over 50% of COVID-19 patients. Liver injury in COVID-19 patients could be attributed to the cytopathic effects induced by the interation between the virus and hepatic cells, exacerbated immune responses or treatment-associated drug toxicity. Here we demonstrate that primary hepatocytes are susceptible to infection in different models: hepatocytes derived from humanized angiotensin-converting enzyme-2 (hACE-2) mice and THLE-2 human cells. Pseudotyped viral particles engineered to express the full-length spike of SARS-CoV-2 and recombinant RBD bind to ACE2 expressed by hepatocytes, promoting metabolic reprogramming towards glycolysis but also mitochondrial dysfunction. In the context of non-alcoholic steatohepatitis (NASH), steatotic hepatocytes derived from hACE2 mice are more vulnerable to infection, as a result of increased expression of ACE2. Metformin, a common therapeutic option for hyperglycemia in type 2 diabetes (T2D) patients, prevents the interaction between the spike of SARS-CoV-2 and steatotic hepatocytes by reducing the expression of hACE2. In summary, we provide evidence that hepatocytes are amenable to SARS-CoV-2 infection and propose metformin as a therapeutic strategy to prevent liver dysfunction caused by SARS-CoV-2 in the context of NASH.

2022-10-14 | PXD035263 | Pride

Multi-Modal Comparison of human Hepatic Stellate Cells identifies novel therapeutic targets for Metabolic Dysfunction-Associated Steatotic Liver Disease

Project description:Background and aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) progresses from steatosis (Metabolic dysfunction-associated steatotic liver, MASL) to Metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis. Activation of Hepatic Stellate Cells (HSCs) into fibrogenic myofibroblasts plays a critical role in the pathogenesis of MASH liver fibrosis. Here we compared gene expression and chromatin accessibility profiles of human HSCs in NORMAL, MASL, and MASH livers at single cell resolution. Methods: 18 human livers were profiled using single-nucleus (sn) RNA-seq and snATAC-seq. High priority targets were identified and then tested in 2D human HSCs, 3D human liver spheroids, and HSC-specific gene knockout mice. Results: This study identified novel gene regulatory mechanisms underlying MASL- and MASH-associated HSC heterogeneity and outlined potential strategies for anti-fibrotic therapy. Specifically, MASH-enriched HSC-subcluster hA1, represented by highly fibrogenic population of myofibroblasts, served as a critical source of extracellular matrix protein (ECM) in MASH, and its activation was regulated via a cross-talk between lineage-specific (JUNB/AP1), cluster-specific (RUNX1/2) and signal-specific (FOXA1/2) transcription factors (TFs). Additionally, we identified a set of core genes (GAS7, SPON1, SERPINE1, LTBP2, KLF9, EFEMP1) that drive ECM production in hA1 HSCs. The pathological relevance of the selected hA1 targets, such as SERPINE1 and others, was demonstrated using siRNA-based HSC-specific gene knockdown or pharmacological inhibitor of SERPINE1 in 3D human MASH liver spheroids, and HSC-specific Serpine1 knockout mice with MASH. Conclusion: We identified potential targets for anti-fibrotic therapy of MASH in patients.

2024-11-13 | GSE244832 | GEO

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

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

| PRJNA1134666 | ENA

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

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