New lean MASH mouse model could guide more targeted liver disease treatment in humans

Mice fed high levels of liquid fructose and salt developed symptoms associated with metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), respectively, according to new research published in Molecular Metabolism.

MASLD, formerly known as nonalcoholic fatty liver disease, is the most prevalent chronic liver disease in the world and can progress to MASH, cirrhosis and liver cancer, the authors noted.

Although MASLD is closely tied to obesity, prior studies cited in the paper estimate that approximately 19% of MASLD patients are lean and that 39% of lean MASLD patients have MASH. Lean patients have a lower risk of type 2 diabetes, dyslipidemia and cardiovascular disease than their obese counterparts but a higher risk of all-cause mortality and liver-related events.

The research was led by Jin Zhou, Ph.D., the Principal Research Scientist at Duke-NUS Medical School Cardiovascular & Metabolic Disorders Signature Research Program. She and her team focused on salt intake because Westernized Asian countries, particularly Singapore, have both a higher prevalence of lean MASLD and higher salt consumption than other countries.

How the lean MASH mouse model was built

Male mice were fed a normal chow diet, a Western diet with 15% fructose in their drinking water (WDF), or WDF supplemented with 4% or 8% salt for 16 weeks. Both salt-supplemented groups had body weight and fat mass comparable to control mice, and the glucose intolerance seen with WDF improved.

Liver weight and triglyceride content were lower in the salt groups than in the fructose group, though liver fat remained higher than in controls, a mild steatosis pattern often seen in lean MASH patients. Portal inflammation and fibrosis, however, were comparable to the WDF group. Researchers described the model in a news release as the first diet-induced mouse model of lean MASH.

Urea cycle and EIF5A hypusination findings

To explain the lower liver fat, researchers looked at the urea cycle, a liver process the body ramps up under high salt intake to conserve water. The Western diet slowed the cycle, and adding salt restored it.

That rebound appears to set off a chain reaction. Its byproducts are used to make spermidine, which activates a protein called EIF5A through a process known as hypusination. Activated EIF5A helps the liver produce mitochondrial proteins that burn fat. Salt-fed mice had more activated EIF5A, more of those proteins and signs of increased fat burning.

High salt amplified liver immune responses

Despite less fat, salt-fed mice had liver inflammation and scarring. An analysis of gene activity in more than 82,000 liver cells found salt made several immune cell types more inflammatory than the Western diet alone. In lab-grown immune cells, salt plus a saturated fat triggered more inflammation and scarring-related gene activity than either alone.

What lean MASH research means for treatment in humans

“Our findings suggest that lean MASH is not simply the same disease occurring in a thinner person. The biology appears to be different,” Zhou said in the news release. “While obesity-associated MASH is closely linked to excess fat accumulation, our model shows that high dietary salt can alter liver metabolism and activate inflammatory pathways even without obesity. That distinction matters because treatments developed for obesity-associated MASH may not address what is driving disease in lean patients.”

The FDA approved Novo Nordisk's Wegovy (semaglutide) last year for adults with noncirrhotic MASH and moderate to advanced liver fibrosis, according to the company, joining Madrigal Pharmaceuticals' Rezdiffra (resmetirom), the first therapy approved for the condition.