A new dietary rat model fully recapitulates metabolic dysfunction-associated steatotic liver disease pathophysiology and mimics human disease with advanced liver fibrosis and portal hypertension

Background and Aims: 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) pathophysiology and mimics human disease. Dietary models are considered the most reliable in terms of reproducing human disease; however, no dietary rodent model has been reported in the proximity of human MASLD, allowing the study of the pathophysiology and treatment strategies for advanced fibrosis and portal hypertension. Approach and Results: We conducted a multistep process of continuous 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, to which adding cholic acid at low concentrations (0.1%) substantially increased the percentage of individuals achieving significant fibrosis at the endpoint. Conclusions Owing to its short duration, simplicity, versatility, and proximity to human MASLD, the proposed model could potentially serve a wide range of investigators working in the field of metabolism and liver disease, allowing significant advances in mechanistic insights into drug development.