Transciptome profile of liver tissues from CD163KO mice after 8 weeks of Western diet.
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE305484 | GEO | 2025/10/01
REPOSITORIES: GEO
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Project description:Background: Western diet (WD) fed Melanocortin 4 receptor-knockout (MC4R-KO) mice develop a phenotype resembling human metabolic dysfunction-associated steatohepatitis (MASH). Despite its clinical relevance, the role of the gut–liver axis in MASH pathogenesis remains unclear. This study investigated the gut-liver axis through microbiomic and metabolomic analyses of WD-fed MC4R-KO mice, and examined their association with MASH pathology. Methods: We performed an integrated microbiome and metabolome analysis of the liver, small intestinal contents, large intestinal contents, and plasma of wild-type (WT) and MC4R-KO mice fed either a normal diet or WD. Markers of hepatic inflammation, fibrosis, and steatosis measured in this study were used to assess MASH severity and to correlate microbiome and metabolite alterations. Results: WD-fed MC4R-KO mice exhibited significant hepatic steatosis, inflammation, and fibrosis. The abundance of certain microbiota, including Muribaculaceae and Allobaculum, negatively correlated with MASH severity, whereas increased levels of Desulfovibrionaceae and Bacteroides positively correlated with hepatic lipid accumulation, steatosis, and inflammation. Metabolomic profiling revealed increased triglyceride and diglyceride levels in the liver and a concomitant decrease in free fatty acids and monoglycerides in the intestines. Additionally, plasma taurine-conjugated bile acids were elevated in WD-fed MC4R-KO mice, which correlated with the reduced hepatic transport of bile salts from pathway enrichment analysis. These findings highlight substantial alterations in the gut microbiota and lipid and bile acid metabolism, indicating a mechanistic dysregulation of the gut–liver axis that may contribute to MASH progression. Conclusions: The observed gut microbial and metabolic alterations, particularly bile acid and lipid metabolism dysregulation, offer insights into potential therapeutic targets aimed at modulating the gut–liver axis to treat or prevent MASH.
2026-03-05 | GSE316452 | GEO
Project description:Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are liver disorders strongly associated with cardiovascular disease (CVD). The PWK/PhJ mouse strain is an emerging model for severe MASH, highly susceptible to Western diet (WD) and closely mimicking the clinical and molecular profile of human MASH. Here, we demonstrate that male and female PWK/PhJ mice exhibit accelerated hepatic fibrosis and cardiac dysfunction following a WD challenge. Elevated cholesterol levels and altered transcript profiles associated with translation and lipid metabolism characterize the early metabolic changes induced by WD. Chronic exposure to WD exacerbates hepatic lipid accumulation, inflammation, and fibrosis, disrupts amino acid metabolism, and increases ceramides and deoxy-ceramides synthesis. We propose that these hepatic changes contribute to the cardiac dysfunction observed in PWK/PhJ mice and may be closely associated with an elevated risk of CVD, thus, positioning the PWK/PhJ strain as a robust model for investigating liver-heart disease connection.
2026-04-20 | GSE309251 | 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:MASLD, especially its severe form MASH, progresses to liver fibrosis, leading to cirrhosis and liver cancer. The crosstalk between spleen and liver in MASLD/MASH progression remains poorly understood. Here, we find the enlarged spleens in MASLD patients, and the induced TRNP1hiCD8+ T cells in the spleens of MASLD/MASH mouse models and confirmed in MASLD patients, with pro-fibrotic property by secreting INSR-α. Mechanistically, demethylated DNA and H3K27me3, increased H3K27ac, together with bolstered enhancer-promoter contact, synergistically reorganized chromatin topologically associating domains spatially to initiate the expression of transcription factor TRNP1 in splenic CD8+ T cells. TRNP1 then transcriptionally activates the expression of FURIN and CTSD, promoting the maturation and ectodomain shedding of INSR-α thereby facilitating its secretion to activate hepatic stellate cells. In vivo blockade of INSR-α using neutralizing antibodies alleviates MASLD/MASH-induced liver fibrosis. Therefore, this study reveals splenic TRNP1hiCD8+ T cells with pro-fibrotic property and suggests a potential anti-fibrotic strategy.
2026-04-30 | GSE295165 | GEO
Project description:MASLD, especially its severe form MASH, progresses to liver fibrosis, leading to cirrhosis and liver cancer. The crosstalk between spleen and liver in MASLD/MASH progression remains poorly understood. Here, we find the enlarged spleens in MASLD patients, and the induced TRNP1hiCD8+ T cells in the spleens of MASLD/MASH mouse models and confirmed in MASLD patients, with pro-fibrotic property by secreting INSR-α. Mechanistically, demethylated DNA and H3K27me3, increased H3K27ac, together with bolstered enhancer-promoter contact, synergistically reorganized chromatin topologically associating domains spatially to initiate the expression of transcription factor TRNP1 in splenic CD8+ T cells. TRNP1 then transcriptionally activates the expression of FURIN and CTSD, promoting the maturation and ectodomain shedding of INSR-α thereby facilitating its secretion to activate hepatic stellate cells. In vivo blockade of INSR-α using neutralizing antibodies alleviates MASLD/MASH-induced liver fibrosis. Therefore, this study reveals splenic TRNP1hiCD8+ T cells with pro-fibrotic property and suggests a potential anti-fibrotic strategy.
2026-04-30 | GSE295162 | GEO
Project description:MASLD, especially its severe form MASH, progresses to liver fibrosis, leading to cirrhosis and liver cancer. The crosstalk between spleen and liver in MASLD/MASH progression remains poorly understood. Here, we find the enlarged spleens in MASLD patients, and the induced TRNP1hiCD8+ T cells in the spleens of MASLD/MASH mouse models and confirmed in MASLD patients, with pro-fibrotic property by secreting INSR-α. Mechanistically, demethylated DNA and H3K27me3, increased H3K27ac, together with bolstered enhancer-promoter contact, synergistically reorganized chromatin topologically associating domains spatially to initiate the expression of transcription factor TRNP1 in splenic CD8+ T cells. TRNP1 then transcriptionally activates the expression of FURIN and CTSD, promoting the maturation and ectodomain shedding of INSR-α thereby facilitating its secretion to activate hepatic stellate cells. In vivo blockade of INSR-α using neutralizing antibodies alleviates MASLD/MASH-induced liver fibrosis. Therefore, this study reveals splenic TRNP1hiCD8+ T cells with pro-fibrotic property and suggests a potential anti-fibrotic strategy.
2026-04-30 | GSE295188 | GEO
Project description:MASLD, especially its severe form MASH, progresses to liver fibrosis, leading to cirrhosis and liver cancer. The crosstalk between spleen and liver in MASLD/MASH progression remains poorly understood. Here, we find the enlarged spleens in MASLD patients, and the induced TRNP1hiCD8+ T cells in the spleens of MASLD/MASH mouse models and confirmed in MASLD patients, with pro-fibrotic property by secreting INSR-α. Mechanistically, demethylated DNA and H3K27me3, increased H3K27ac, together with bolstered enhancer-promoter contact, synergistically reorganized chromatin topologically associating domains spatially to initiate the expression of transcription factor TRNP1 in splenic CD8+ T cells. TRNP1 then transcriptionally activates the expression of FURIN and CTSD, promoting the maturation and ectodomain shedding of INSR-α thereby facilitating its secretion to activate hepatic stellate cells. In vivo blockade of INSR-α using neutralizing antibodies alleviates MASLD/MASH-induced liver fibrosis. Therefore, this study reveals splenic TRNP1hiCD8+ T cells with pro-fibrotic property and suggests a potential anti-fibrotic strategy.
2026-04-30 | GSE295187 | GEO
Project description:MASLD, especially its severe form MASH, progresses to liver fibrosis, leading to cirrhosis and liver cancer. The crosstalk between spleen and liver in MASLD/MASH progression remains poorly understood. Here, we find the enlarged spleens in MASLD patients, and the induced TRNP1hiCD8+ T cells in the spleens of MASLD/MASH mouse models and confirmed in MASLD patients, with pro-fibrotic property by secreting INSR-α. Mechanistically, demethylated DNA and H3K27me3, increased H3K27ac, together with bolstered enhancer-promoter contact, synergistically reorganized chromatin topologically associating domains spatially to initiate the expression of transcription factor TRNP1 in splenic CD8+ T cells. TRNP1 then transcriptionally activates the expression of FURIN and CTSD, promoting the maturation and ectodomain shedding of INSR-α thereby facilitating its secretion to activate hepatic stellate cells. In vivo blockade of INSR-α using neutralizing antibodies alleviates MASLD/MASH-induced liver fibrosis. Therefore, this study reveals splenic TRNP1hiCD8+ T cells with pro-fibrotic property and suggests a potential anti-fibrotic strategy.
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Project description:MASLD, especially its severe form MASH, progresses to liver fibrosis, leading to cirrhosis and liver cancer. The crosstalk between spleen and liver in MASLD/MASH progression remains poorly understood. Here, we find the enlarged spleens in MASLD patients, and the induced TRNP1hiCD8+ T cells in the spleens of MASLD/MASH mouse models and confirmed in MASLD patients, with pro-fibrotic property by secreting INSR-α. Mechanistically, demethylated DNA and H3K27me3, increased H3K27ac, together with bolstered enhancer-promoter contact, synergistically reorganized chromatin topologically associating domains spatially to initiate the expression of transcription factor TRNP1 in splenic CD8+ T cells. TRNP1 then transcriptionally activates the expression of FURIN and CTSD, promoting the maturation and ectodomain shedding of INSR-α thereby facilitating its secretion to activate hepatic stellate cells. In vivo blockade of INSR-α using neutralizing antibodies alleviates MASLD/MASH-induced liver fibrosis. Therefore, this study reveals splenic TRNP1hiCD8+ T cells with pro-fibrotic property and suggests a potential anti-fibrotic strategy.
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Project description:MASLD, especially its severe form MASH, progresses to liver fibrosis, leading to cirrhosis and liver cancer. The crosstalk between spleen and liver in MASLD/MASH progression remains poorly understood. Here, we find the enlarged spleens in MASLD patients, and the induced TRNP1hiCD8+ T cells in the spleens of MASLD/MASH mouse models and confirmed in MASLD patients, with pro-fibrotic property by secreting INSR-α. Mechanistically, demethylated DNA and H3K27me3, increased H3K27ac, together with bolstered enhancer-promoter contact, synergistically reorganized chromatin topologically associating domains spatially to initiate the expression of transcription factor TRNP1 in splenic CD8+ T cells. TRNP1 then transcriptionally activates the expression of FURIN and CTSD, promoting the maturation and ectodomain shedding of INSR-α thereby facilitating its secretion to activate hepatic stellate cells. In vivo blockade of INSR-α using neutralizing antibodies alleviates MASLD/MASH-induced liver fibrosis. Therefore, this study reveals splenic TRNP1hiCD8+ T cells with pro-fibrotic property and suggests a potential anti-fibrotic strategy.
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