Western diet-induced MASH in PWK/PhJ mice identifies disruptions in amino acid and sphingolipid metabolism contributing to cardiac dysfunction

Abstract Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are liver disorders strongly associated with cardiovascular disease (CVD). The PWK/PhJ mouse strain is an emerging model for severe MASH, highly susceptible to Western diet (WD) and closely mimicking the clinical and molecular profile of human MASH. Here, we demonstrate that male and female PWK/PhJ mice develop hepatic fibrosis and cardiac dysfunction after 17 weeks of WD challenge. Elevated cholesterol levels and altered transcript profiles associated with translation and lipid metabolism characterize the early metabolic changes induced by WD. Chronic exposure to WD exacerbates hepatic lipid accumulation, inflammation, and fibrosis, while disrupting amino acid and mitochondrial metabolism. These alterations increase hepatic synthesis of ceramides and deoxy-ceramides, contributing to elevated sphingolipid levels in plasma and heart tissue. Collectively, these metabolic changes drive the development of MASH and significantly increase CVD risk. Our findings establish the PWK/PhJ strain as a robust model to study cardio-metabolic cross talk and identifying therapeutic targets for cardio-metabolic disorders.