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Western diet-induced MASH in PWK/PhJ mice identifies disruptions in amino acid and sphingolipid metabolism contributing to cardiac dysfunction

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE309251 | GEO | 2026/04/20

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.

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Western diet-induced MASH in PWK/PhJ mice identifies disruptions in amino acid and sphingolipid metabolism contributing to cardiac dysfunction

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