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High salt supplementation of a MASH-inducing diet causes lean MASH phenotype with increased hepatic urea cycle activity and EIF5A hypusination

ABSTRACT: MASLD/MASH can occur in lean individuals; however, the environmental triggers and molecular mechanisms of lean MASH are unclear, and suitable animal models are lacking. Western diet + fructose (WDF) causes obesity and MASH. Surprisingly, high salt supplementation of WDF (HSWDF) produced a lean MASH phenotype with significant inflammation and fibrosis, and reduced steatosis. Interestingly, we observed decreased urea cycle activity leading to reduced eukaryotic translation initiation factor 5A hypusination (Eif5aH) and impaired mitochondrial protein synthesis in mice fed WDF. High saltsupplementation unexpectedly improved these changes to improve hepatic fatty acid oxidation and steatosis. Additionally, single-cell sequencing revealed that high salt induced pro-inflammatory responses in hepatic immune cell subpopulations. In summary, we have established a dietary mouse model of lean MASH with key effects on the hepatic urea cycle, mitochondrial protein synthesis, and immune cell activation. Our findings suggest salt restriction may be beneficial in some patients with lean MASH.

ORGANISM(S): Mus musculus

PROVIDER: GSE315305 | GEO | 2026/07/29

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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High salt supplementation of a MASH-inducing diet causes lean MASH phenotype with increased hepatic urea cycle activity and EIF5A hypusination

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