New research published in Molecular Metabolism reveals a lean mouse model for metabolic dysfunction-associated steatohepatitis (MASH), a severe form of liver disease. The study highlights the growing recognition of MASH in lean individuals, who comprise approximately 19% of MASLD patients, with 39% of these lean cases progressing to MASH.
Diet-induced model mimics lean MASH in mice
Researchers fed male mice a Western diet with high fructose and varying salt levels. Mice on the high-salt diet developed liver inflammation and scarring, despite having less liver fat than those on a fructose-only diet. This mirrors the condition in lean human patients with MASH. Specifically, the mice were given a Western diet with 15% fructose in their drinking water (WDF), supplemented with either 4% or 8% salt for 16 weeks. While their body weight and fat mass remained comparable to control mice, they exhibited liver changes characteristic of lean MASH, including a mild steatosis pattern and significant portal inflammation and fibrosis.
The team, led by Jin Zhou of Duke-NUS Medical School, focused on salt intake due to its higher consumption in Westernized Asian countries like Singapore, where lean MASH is more prevalent. Zhou noted that these countries have both a higher incidence of lean MASLD and greater salt consumption compared to other regions, making salt a critical factor to investigate.
Salt triggers unique metabolic changes
High salt intake activated the urea cycle, a liver process that conserves water. This led to increased production of spermidine, which in turn activated a protein called EIF5A. Activated EIF5A boosted the liver’s ability to burn fat, explaining the lower liver fat in salt-fed mice. The Western diet initially slowed the urea cycle, but adding salt restored it, triggering a chain reaction that increased spermidine levels and EIF5A activation. This process enhanced mitochondrial function, promoting fat burning in the liver.
These findings suggest that lean MASH may involve distinct biological mechanisms compared to obesity-associated MASH. As a result, different treatment approaches might be necessary. 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.
Implications for human treatment
Currently approved treatments for MASH, such as Novo Nordisk’s Wegovy and Madrigal Pharmaceuticals’ Rezdiffra, target obesity-associated MASH. Zhou notes that these treatments may not work for lean patients due to the disease’s different underlying biology. The FDA approved Wegovy for adults with noncirrhotic MASH and moderate to advanced liver fibrosis.
