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

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 exhibit accelerated hepatic fibrosis and cardiac dysfunction following a 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, disrupts amino acid metabolism, and increases ceramides and deoxy-ceramides synthesis. We propose that these hepatic changes contribute to the cardiac dysfunction observed in PWK/PhJ mice and may be closely associated with an elevated risk of CVD, thus, positioning the PWK/PhJ strain as a robust model for investigating liver-heart disease connection.