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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

GSE315305 Mus musculus Expression profiling by high throughput sequencing 4 samples Submitted 2026/07/29 Platform GPL24247
Summary
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.
Published in
High salt supplementation of a MASH-inducing diet causes lean MASH phenotype with increased hepatic urea cycle activity and EIF5A hypusination
Luo S, Morisawa N, Widjaja AA et al. · Molecular metabolism 2026 · PMID 42419570 · doi:10.1016/j.molmet.2026.102417
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Also filed as BioProject PRJNA1395603 and SRA study SRP658948. Searching any of these in the dataset finder brings you back here.

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