Antigen-driven CD8+ T cell clonal expansion is a prominent feature of MASH in humans and mice [mouse]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE270490 | GEO | 2025/01/22
REPOSITORIES: GEO
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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 human sequencing data.
2025-01-22 | GSE270488 | 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:Proteomics profiling of enriched Cytoplasmic and Peridroplet mitochondria from healthy and diet-induced MASLD/MASH mouse models
2025-01-20 | PXD052526 | Pride
Project description:Recent findings reveal the importance of tryptophan-initiated de novo nicotinamide adenine dinucleotide (NAD+) synthesis in the liver, a process previously considered secondary to biosynthesis from nicotinamide. Here we show that inhibiting α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) promotes de novo NAD+ synthesis and reduces DNA damage ex vivo, in vivo and in human liver organoid (HLO) models. In mouse models of MASLD/MASH, de novo NAD+ biosynthesis is suppressed, and transcriptomic DNA damage signatures correlate with disease severity; In humans, Mendelian randomization-based genetic analysis suggests a notable impact of genomic stress on liver disease susceptibility. Therapeutic inhibiting ACMSD in mice elevates liver NAD+ and reverses MASLD/MASH, mitigating fibrosis, inflammation and DNA damage. Similar outcomes are recapitulated in HLO models of steatohepatitis and DNA damage. Our findings highlight the benefits of ACMSD inhibition for boosting hepatic NAD+ and genomic protection, indicating its therapeutic promise in liver diseases marked by NAD+ and genomic stress.
2024-09-22 | GSE253217 | GEO
Project description:Recent findings reveal the importance of tryptophan-initiated de novo nicotinamide adenine dinucleotide (NAD+) synthesis in the liver, a process previously considered secondary to biosynthesis from nicotinamide. Here we show that inhibiting α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) promotes de novo NAD+ synthesis and reduces DNA damage ex vivo, in vivo and in human liver organoid (HLO) models. In mouse models of MASLD/MASH, de novo NAD+ biosynthesis is suppressed, and transcriptomic DNA damage signatures correlate with disease severity; In humans, Mendelian randomization-based genetic analysis suggests a notable impact of genomic stress on liver disease susceptibility. Therapeutic inhibiting ACMSD in mice elevates liver NAD+ and reverses MASLD/MASH, mitigating fibrosis, inflammation and DNA damage. Similar outcomes are recapitulated in HLO models of steatohepatitis and DNA damage. Our findings highlight the benefits of ACMSD inhibition for boosting hepatic NAD+ and genomic protection, indicating its therapeutic promise in liver diseases marked by NAD+ and genomic stress.
2024-09-23 | GSE253380 | GEO
Project description:Non-alcoholic steatohepatitis (NASH) represents a significant and growing public health concern worldwide, characterized by hepatic steatosis, inflammation, and varying degrees of fibrosis. In vitro models of NASH play a crucial role in elucidating the underlying mechanisms of disease pathogenesis, identifying potential therapeutic targets, and evaluating the efficacy of pharmacological interventions. Several preclinical models of MASH have been developed and are being used extensively to study these areas. While standard cell culture models allow for elucidation of certain molecular pathways involved in MASH pathogenesis, they lack three-dimensional architecture and cellular heterogeneity observed in native liver tissue, potentially limiting their physiological relevance and inability to fully capture the multifactorial nature of the disease Precision cut liver slices from MASH livers retain the complex multicellular architecture of the liver including hepatocyte arrangement, sinusoidal structure, and cellular interactions, but the metabolism deteriorates over a short period of time (usually reported as 2 days). Human liver organoids from iPSCs (induced pluripotent stem cells) retain the genetics of the patients but fail to fully differentiate into hepatocytes or have the liver architecture. Human liver spheroids incubated in a MASH cocktail develop several phenotypic characteristics of a MASH liver, but the small spheroid size precludes extensive histological comparisons to MASH livers. Microphysiological systems (MPS) or “liver on a chip” in which 3D cultures are perfused, maintain many of the physiological functions of the liver owing to precise control over microenvironmental parameters, including fluid flow, nutrient gradients, and mechanical cues. However, MPS are difficult to scale up and have not been developed to reproduce a MASH phenotype. In comparison, bioprinted liver tissues for MASH have many advantages. Organovo’s 3D bioprinted liver tissues are comprised of all major primary liver cells including hepatocytes, endothelial cells, stellates and Kupffer cells, mixed in physiologically relevant ratios. These cells are then bioprinted in precise pre-defined liver specific geometries to recapitulate complexity of the hepatic microenvironment.. This mimicking of tissue architecture enables more accurate representation of cellular interactions, spatial organization, and microenvironmental cues crucial for MASH pathogenesis. The liver tissues developed using this method maintain differentiation and metabolism over several weeks. In this paper, we further demonstrated that upon treatment with a MASH induction cocktail, these liver tissues respond accurately by developing steatosis and fibrosis Tissue response varies depending in response to the complexity of the MASH cocktail.
2024-11-29 | GSE280378 | GEO
Project description:Liver x receptor alpha (LXRα, Nr1h3) functions as an important intracellular cholesterol sensor that regulates liver fat and cholesterol metabolism at the transcriptional level in response to the direct binding of cholesterol derivatives. We have generated mice with a mutation in LXRα that reduces activity in response to endogenous cholesterol derived LXR ligands while still allowing transcriptional activation by synthetic agonists. The mutant LXRα functions as a dominant negative that shuts down cholesterol sensing. When fed a high fat, high cholesterol diet LXRα mutant mice rapidly develop pathologies associated with Metabolic Dysfunction-Associated Steatohepatitis (MASH) including ballooning hepatocytes, liver inflammation, and fibrosis. Strikingly LXRα mutant mice have decreased liver triglycerides but increased liver cholesterol. Therefore, MASH-like phenotypes can arise in the absence of large increases in hepatic triglycerides. Reengaging LXR signaling by treatment with synthetic agonist reverses MASH suggesting that LXRα normally functions to impede the development of liver disease.
2024-06-06 | GSE267011 | GEO
Project description:Metabolic-associated steatohepatitis (MASH), the inflammatory stage of MASLD, will soon be one of the primary causes of liver-related complications, including advanced fibrosis and hepatocellular carcinoma. Its steady increase in both the US and the global population is devastating. Between the two genders, more women are suffering from MASH compared to the man due to estrogen deficiency caused by polycystic ovary syndrome or menopause. Our published data shows a clear positive association between the progression of liver disease and the expression of novel hexokinase HKDC1 in the liver. Targeting HKDC1, which is highly expressed in pathological hepatocytes (in MASH) but negligible in normal hepatocytes, represents a highly selective approach. Therefore, we hypothesized that liver-specific deletion of HKDC1 will protect against diet-induced obesity and the progression of MASH to fibrosis. We used an early-onset liver knockout (LKO) of HKDC1 by crossing HKDC1 floxed mice with Albumin Cre mice to test our hypothesis. We fed the Western Diet to HKDC1LKO female mice along with HKDC1 floxed mice (HKDC1fl/fl; as Controls) for 28 weeks. Our data shows that HKDC1 deletion significantly decreases body weight and fat mass compared to HKDC1fl/fl mice with no changes in food intake and energy expenditure. Knockout mice have better glucose tolerance and lower fasting glucose levels than HKDC1fl/fl mice. Our data also shows that the knockout group has smaller livers, healthier liver parameters, less steatosis, and lower NAS and fibrosis scores. Furthermore, HKDC1 knockout alters hepatic gene expression, and we found significantly low proinflammatory and profibrogenic gene expression in the LKO mice. Although we did not see any changes in triglyceride levels, there was a significant reduction of serum cholesterol concomitant with enhanced expression of cholesterol metabolism genes in the knockout group. Our data suggest a promising protective role of HKDC1 deletion against diet-induced obesity and MASH mice.
2024-11-27 | GSE283058 | 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