Development and characterization of dietary models of MASLD with portal hypertension and liver fibrosis in rats.

Abstract

For decades, investigators have pursued the development of a comprehensive rodent model that fully recapitulates the pathophysiology of metabolic dysfunction-associated steatotic liver disease (MASLD) and mimics human disease. Dietary models are generally considered the most reliable for recapitulating human disease; however, no dietary rodent model has yet been reported with high similarity to human MASLD, limiting the study of pathophysiology and treatment strategies for advanced fibrosis and portal hypertension. Here we conducted a multistep, sequential refinement of our MASLD model in rats until we achieved a comprehensive model that reproduced the clinical features of metabolic syndrome, steatohepatitis, advanced fibrosis and portal hypertension with a transcriptomic profile resembling human MASLD. The final model consisted of a 20-week high-fat diet with high concentrations of cholesterol (2%) and a glucose-fructose beverage; in this model, the addition of cholic acid at low concentrations (0.1%) substantially increased the percentage of rats achieving fibrosis stage ≥F2 at the endpoint. Owing to its short duration, simplicity, versatility and strong translational relevance to human MASLD, the proposed model could potentially serve a wide range of investigators working in the field of metabolism and liver disease, facilitating meaningful advances in mechanistic studies and the development of new therapeutics.