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Transcriptomic alterations associated with the progression of metabolic dysfunction-associated steatotic liver disease in CC042 Collaborative Cross mice.

ABSTRACT: Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as nonalcoholic fatty liver disease, has emerged as the most common chronic liver disease globally, affecting more than one-third of the world’s population. Its rate has increased by 13%, rising from 25% to 38% over the past three decades. MASLD is characterized by excessive fat accumulation in hepatocytes and, if left untreated, progresses to its more severe form, metabolic dysfunction-associated steatohepatitis (MASH), which poses a significant global health concern as one of the leading causes of cirrhosis, cirrhotic complications, and hepatocellular carcinoma. The molecular determinants of MASLD stratification are not clearly defined and require additional investigation. In this study, we used male and female CC042 mice, a Collaborative Cross mouse strain susceptible to the development of MASLD, to analyze the global transcriptomic profile in liver and to clarify the molecular mechanisms involved in the progression of the disease. Male and female CC042 mice were maintained on a high fat/high sucrose (HF/HS) diet for 20, 40, or 60 weeks, and hepatic gene expression profiles were determined by next-generation RNA sequencing. Chronic feeding of the HF/HS diet induced profound alterations in gene expression at all time points. The number of significantly differentially expressed genes (DEGs) in the livers of male mice was greater than female mice at 20 and 40 weeks and reached a maximum of 2764 genes at 40 weeks. In contrast, the number of DEGs in the livers of female mice steadily increased with the time on diet reaching a maximum of 2974 DEGs at 60 weeks after HF/HS diet initiation. The number of upregulated DEGs was higher than downregulated DEGs in both male and female mice at all time points. Functional analysis of DEGs showed that in both sexes, the most dysregulated liver toxicity-related pathways were associated with liver fibrosis, liver necrosis/cell death, inflammation, steatosis, liver damage, and liver proliferation/hyperplasia. In male mice, pathways associated with fibrosis, necrosis/cell death, inflammation, and steatosis remained constant from 20 to 40 weeks, and activation of liver hyperplasia pathway was constant from 40 and 60 weeks. In contrast, in female mice, dysregulation of genes associated with these pathways gradually increased from 20 to 60 weeks after HF/HS diet initiation. Importantly, we found that the expression of 701 and 871 genes significantly correlated with total NASH pathology scores (Pearson r > |0.8|) in the livers of male and female mice, respectively. These findings provide comprehensive insights into the dynamics of time- and sex-specific transcriptomic changes during NAFLD progression. This knowledge can be helpful for identifying promising targets for prevention and treatment, as well as for determining key potential biomarkers of NAFLD to NASH progression.

ORGANISM(S): Mus musculus

PROVIDER: GSE275176 | GEO | 2025/07/09

REPOSITORIES: GEO

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Project description:High-protein diets are known to reduce adiposity in the context of high carbohydrate and Western diets. However, few studies have investigated the specific high-protein effect on lipogenesis induced by a high-sucrose (HS) diet or fat deposition induced by high-fat feeding. We aimed to determine the effects of high protein intake on the development of fat deposition and partitioning in response to high-fat and/or HS feeding. A total of thirty adult male Wistar rats were assigned to one of the six dietary regimens with low and high protein, sucrose and fat contents for 5 weeks. Body weight (BW) and food intake were measured weekly. Oral glucose tolerance tests and meal tolerance tests were performed after 4th and 5th weeks of the regimen, respectively. At the end of the study, the rats were killed 2 h after ingestion of a calibrated meal. Blood, tissues and organs were collected for analysis of circulating metabolites and hormones, body composition and mRNA expression in the liver and adipose tissues. No changes were observed in cumulative energy intake and BW gain after 5 weeks of dietary treatment. However, high-protein diets reduced by 20 % the adiposity gain induced by HS and high-sucrose high-fat (HS-HF) diets. Gene expression and transcriptomic analysis suggested that high protein intake reduced liver capacity for lipogenesis by reducing mRNA expressions of fatty acid synthase (fasn), acetyl-CoA carboxylase a and b (Acaca and Acacb) and sterol regulatory element binding transcription factor 1c (Srebf-1c). Moreover, ketogenesis, as indicated by plasma β-hydroxybutyrate levels, was higher in HS-HF-fed mice that were also fed high protein levels. Taken together, these results suggest that high-protein diets may reduce adiposity by inhibiting lipogenesis and stimulating ketogenesis in the liver. Adult male Wistar rats were fed diets with varying amounts of protein, carbohydrates and fat for 5 weeks. At the end of the experiment, rats were killed and tanscriptome analysis was performed on pooled liver samples.

Project description:Background: Consumption of high fat diets has negative impacts on health and well-being, some of which may be epigenetically regulated. Selenium and folate are two compounds which influence epigenetic mechanisms. We investigated the hypothesis that post-weaning supplementation with adequate levels of selenium and folate in mouse offspring fed a high fat, low selenium and folate diet during gestation and lactation will lead to epigenetic changes of potential importance for long-term health. Female offspring of mothers fed the experimental diet were either maintained on this diet (HF-low-low), or weaned onto a high-fat diet with sufficient levels of selenium and folate (HF-low-suf), for 8 weeks. Gene and protein expression, DNA methylation, and histone modifications were measured in colon and liver of female offspring. Results: Adequate levels of selenium and folate post-weaning affected gene expression in colon and liver of offspring, including decreasing Slc2a4 gene expression. Protein expression was only altered in the liver. There was no effect of adequate levels of selenium and folate on global histone modifications in the liver. Global liver DNA methylation was decreased in mice switched to adequate levels of selenium and folate, but there was no effect on methylation of specific CpG sites within the Slc2a4 gene in liver. Conclusions: Post-weaning supplementation with adequate levels of selenium and folate in female offspring of mice fed high-fat diets during gestation and lactation can alter global DNA methylation in liver. This may be one mechanism by which the negative effects of a poor diet during early life can be ameliorated. Further research is required to establish what role epigenetic changes play in mediating observed changes in gene and protein expression, and the relevance of these changes to health. Female wild type C57BL/6 mice (Animal Resource Centre, Western Australia) were fed a High Fat diet containing low levels of selenium and folate (HF-Low) for 7 days prior to mating with male C57BL/6 mice (Ruakura Small Animal Facility, Hamilton, New Zealand). Mothers were maintained on the HF-Low diet throughout gestation and lactation. Offspring of these female mice were randomly assigned to one of two different dietary treatments: either the same diet as the mothers (HF-Low), or a High Fat diet containing adequate selenium and folate (HF-Suf). At 12 weeks of age, mice were euthanized and colon and liver samples taken for microarray, proteomics, and DNA methylation analyses. Genomic DNA, total RNA and protein from whole colon and liver tissue was extracted using an AllPrepM-BM-. DNA/RNA/Protein mini kit (Qiagen, Cat number 80004). Colon and liver RNA from six female offspring on the HF-Low diet was compared with colon and liver RNA from six female offspring on the HF-Suf diet. All individual RNA samples were hybridized against a common reference RNA on separate arrays. The reference RNA was prepared by pooling in equimolar proportions RNA extracted from the intestine and liver of twelve female C57BL/6 mice, these being all of the mice from which samples were derived for microarray analysis in the current study.

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Transcriptomic alterations associated with the progression of metabolic dysfunction-associated steatotic liver disease in CC042 Collaborative Cross mice.

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