Characteristics of liver tissues of MASH compared to those of Simple Steatosis mice.
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE296715 | GEO | 2025/06/19
REPOSITORIES: GEO
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Project description:Characteristics of liver tissues of MASH compared to those of Simple Steatosis mice.
| PRJNA1260808 | ENA
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:Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are characterized by excessive triglyceride accumulation in the liver. However, due to an incomplete understanding of its pathogenesis, more efforts are still needed to identify specific and effective treatments. N4-acetylcytidine (ac4C) is a newly discovered RNA modification to regulate mRNA stability post-transcriptionally. N-acetyltransferase 10 (NAT10), the sole enzyme catalyzing mRNA acetylation, has not been fully explored in human diseases, especially in MASLD and MASH. In the current study, abundant RNA acetylation was found in lipid metabolism-related genes in the livers of leptin receptor-deficient (db/db) mice. Besides, hepatic NAT10 expression is significantly increased in multiple mouse models of MASLD and MASH. NAT10 expression is also elevated in patients with MASLD and positively correlated with clinical characteristics. Genetic NAT10 knockdown protects against diet-induced hepatic steatosis and steatohepatitis in mice, while its overexpression exacerbates steatosis. Mechanistically, NAT10 could bind to Srebp-1c mRNA to promote its stability and expression, thereby upregulating lipogenic enzymes. In addition, the translational significance of our findings is that treatment of Remodelin, an NAT10 inhibitor, could improve liver steatosis and dyslipidemia in a preclinical mouse model. Together, these findings highlight the significance of ac4C modification and NAT10 in MASLD and MASH, offering a potential therapeutic target for disease treatment.
2024-09-22 | GSE275576 | GEO
Project description:Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are characterized by excessive triglyceride accumulation in the liver. However, due to an incomplete understanding of its pathogenesis, more efforts are still needed to identify specific and effective treatments. N4-acetylcytidine (ac4C) is a newly discovered RNA modification to regulate mRNA stability post-transcriptionally. N-acetyltransferase 10 (NAT10), the sole enzyme catalyzing mRNA acetylation, has not been fully explored in human diseases, especially in MASLD and MASH. In the current study, abundant RNA acetylation was found in lipid metabolism-related genes in the livers of leptin receptor-deficient (db/db) mice. Besides, hepatic NAT10 expression is significantly increased in multiple mouse models of MASLD and MASH. NAT10 expression is also elevated in patients with MASLD and positively correlated with clinical characteristics. Genetic NAT10 knockdown protects against diet-induced hepatic steatosis and steatohepatitis in mice, while its overexpression exacerbates steatosis. Mechanistically, NAT10 could bind to Srebp-1c mRNA to promote its stability and expression, thereby upregulating lipogenic enzymes. In addition, the translational significance of our findings is that treatment of Remodelin, an NAT10 inhibitor, could improve liver steatosis and dyslipidemia in a preclinical mouse model. Together, these findings highlight the significance of ac4C modification and NAT10 in MASLD and MASH, offering a potential therapeutic target for disease treatment.
2024-09-22 | GSE275575 | GEO
Project description:Through mass spectrometry, we quantified liver global proteomes of Simple steatosis and Non-alcoholic Steatohepatitis in a HFHC diet induced mouse model
2022-03-24 | PXD032806 |
Project description:Modulation of metabolic, inflammatory, and fibrotic pathways by semaglutide in metabolic dysfunction-associated steatohepatitis Metabolic dysfunction-associated steatohepatitis (MASH) is a chronic liver disease strongly associated with cardiometabolic risk factors. Semaglutide, a glucagon-like peptide-1 receptor agonist, improves liver histology in MASH, but the underlying signals and pathways driving semaglutide-induced MASH resolution are not well understood. We show that, in two preclinical MASH models, semaglutide improved histological markers of fibrosis and inflammation, and reduced hepatic expression of fibrosis- and inflammation-related gene pathways.
2025-04-25 | GSE294629 | GEO
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
Project description:Background & Aims: Metabolic dysfunction associated steatotic liver disease (MAFLD) progresses to steatohepatitis (MASH) and is a major cause of liver cirrhosis. In the early disease stage, liver inflammation is absent. However, the early involvement of the peripheral immune cell compartments in disease progression is poorly understood and single cell profiles of peripheral immune cells in MAFLD/MASH are not known. Methods: MAFLD/MASH patients and healthy volunteers have been prospectively enrolled into a cross-sectional study. Patients have been histologically stratified and characterized by liver bulk RNA-Seq.
2025-04-30 | GSE267031 | GEO
Project description:While macrophage heterogeneity during Metabolic dysfunction-associated steatohepatitis (MASH) has been described, the fate of these macrophages during MASH regression is poorly understood. Comparing macrophage heterogeneity during MASH progression vs regression, we identified specific macrophage sub- populations that are critical for MASH/fibrosis resolution. We elucidated the restorative pathways and gene signatures that define regression associated macrophages (RAM) and establish the importance of TREM2+ macrophages during MASH regression. Liver resident Kupffer cells are lost during MASH and are replaced by four distinct monocyte derived macrophage sub-populations. Trem2 is expressed in two macrophage sub- populations: (i) monocyte-derived macrophages occupying the Kupffer cell niche (MoKC) and (ii) lipid-associated macrophages (LAM). In regression livers, no new transcriptionally distinct MF sub-population emerged. However, the relative macrophage composition changed during regression compared to MASH. While MoKC was the major macrophage sub-population during MASH, they decreased during regression. LAM was the dominant macrophage sub-type during MASH regression and maintained Trem2 expression. Both MoKC and LAM were enriched in disease resolving pathways. Absence of TREM2 restricted the emergence of LAMs and formation of hepatic crown like structures (hCLS). TREM2+ macrophages are functionally important not only for restricting MASH-fibrosis progression, but also for effective regression of inflammation and fibrosis. TREM2+ MF are superior collagen degraders. Lack of TREM2+ macrophages also prevented elimination of hepatic steatosis and inactivation of HSC during regression, indicating their significance in metabolic co-ordination with other cell- types in the liver. TREM2 imparts this protective effect through multifactorial mechanisms, including improved phagocytosis, lipid-handling and collagen degradation.
2024-08-05 | GSE261829 | GEO
Project description:Rates of hepatocellular carcinoma (HCC) are increasing rapidly due to the epidemic of metabolic dysfunction-associated steatohepatitis (MASH). In addition to increased incidence, emerging evidence suggests that MASH driven HCC is associated with poor survival outcomes potentially due to the complex liver microenvironment which is characterized by hypoxia, steatosis, and fibrosis. Lenvatinib, is a multi-tyrosine kinase inhibitor, that is a standard of care therapy for unresected HCC, but 5-year survival rates are less than 20%. Therefore, developing treatments that inhibit cancer growth kinetics and target the tumor microenvironment to improve the therapeutic response in MASH-HCC are needed. Salsalate is a rheumatoid arthritis therapy that stimulates the AMP-activated protein kinase (AMPK) increasing fatty acid oxidation while reducing de-novo lipogenesis, fibrosis and cell proliferation pathways. Thus, we hypothesized that Salsalate could improve the therapeutic efficacy of Lenvatinib in MASH-HCC. In the current study, we show that treatment of human HCC cells with clinically relevant concentrations of Lenvatinib and Salsalate synergistically suppress proliferation and clonogenic survival, activate AMPK and inhibit the mTOR-HIF1a and Erk1/2 signaling pathways. In orthotopic xenograft and MASH-HCC mouse models Lenvatinib and Salsalate combination therapy suppressed angiogenesis and steatosis and fibrosis. RNA-sequencing revealed combination therapy enhanced mitochondria fatty acid oxidation and suppressed glycolysis, angiogenesis, fibrosis and cell cycle progression with regulatory network analysis suggesting a potential role for Activating transcription factor 3 (ATF3) and ETS-proto-oncogene-1 (ETS1). These data suggest that Lenvatinib and Salsalate combination therapy may have therapeutic potential for MASH-HCC due to effective metabolic rewiring and growth inhibition, leading to improvements in the liver microenvironment and inhibition of HCC proliferation.
2025-02-01 | GSE282660 | GEO