Researchers have developed what they described as the first diet-induced mouse model of lean metabolic dysfunction-associated steatohepatitis (MASH), showing that high dietary salt can alter liver metabolism and activate inflammatory pathways even without obesity. While obesity-associated MASH is closely tied to excess fat accumulation, the new findings suggest lean MASH operates through distinct biological mechanisms.
Dietary Salt and Lean MASH Development in Male Mice
For 16 weeks, researchers established the lean MASH model by providing male mice with either a normal chow diet, a Western diet containing 15% fructose in their drinking water (WDF), or WDF that included 4% or 8% salt supplementation.
Both salt-supplemented groups maintained body weight and fat mass comparable to control mice. The glucose intolerance typically observed with the Western diet showed improvement in these salt-fed groups.
Liver weight and triglyceride content were lower in the salt groups than in the fructose-only group. However, liver fat remained higher than in baseline controls, reflecting a mild steatosis pattern frequently observed in lean MASH patients. Portal inflammation and fibrosis in the salt-fed mice remained comparable to the WDF group.
Urea Cycle Restoration and EIF5A Hypusination
To investigate why salt-fed mice had lower liver fat despite retaining inflammation, researchers examined the urea cycle. The body naturally ramps up this liver process during high salt intake to conserve water. While the Western diet slowed the cycle down, adding salt successfully restored it.
This metabolic rebound triggers a chain reaction. The byproducts of the restored urea cycle generate spermidine, which subsequently activates a protein known as EIF5A through hypusination. Activated EIF5A assists the liver in producing mitochondrial proteins dedicated to burning fat. Consequently, salt-fed mice exhibited higher levels of activated EIF5A, increased mitochondrial proteins, and clear biochemical signs of enhanced fat burning.
Salt Exposure Increases Liver Inflammation and Scarring
Despite showing reduced liver fat, salt-fed mice experienced significant liver inflammation and scarring. An analysis of gene activity spanning more than 82,000 liver cells demonstrated that salt exposure increased the inflammatory response across several immune cell types compared to the Western diet alone.
In laboratory tests involving isolated immune cells, the combination of salt and a saturated fat stimulated higher levels of inflammation and scarring-related gene activity than either substance produced individually. Zhou noted in the news release that these findings indicate lean MASH is not simply the same disease occurring in a thinner person, as the underlying biology appears fundamentally different.
Implications for Human Treatment Options
Recognizing that high dietary salt drives disease processes independently of obesity is critical for therapeutic development. Treatments specifically designed for obesity-associated MASH may fail to target the primary drivers of disease in lean patients.
Therapeutic options for MASH continue to expand. According to the company, Novo Nordisk’s Wegovy (semaglutide) received FDA approval last year for adults suffering from moderate to advanced liver fibrosis and noncirrhotic MASH.
How much salt was added to the mouse diets in the study?
Researchers supplemented the Western diet with either 4% or 8% salt in the drinking water for a duration of 16 weeks.
What role does EIF5A play in liver fat metabolism?
Activated EIF5A, driven by spermidine from the restored urea cycle, helps the liver produce specific mitochondrial proteins that burn fat.
Which therapies are currently approved by the FDA for MASH?
Madrigal Pharmaceuticals’ Rezdiffra was approved as the first therapy for the condition, and the FDA subsequently approved Novo Nordisk’s Wegovy for adults with noncirrhotic MASH and moderate to advanced liver fibrosis.
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