New translational mouse models for metabolic dysfunction-associated steatotic liver disease comparable to human MASLD with severe obesity

Objective:
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common cause of chronic liver disease, in particular in patient with severe obesity. However, common mouse models for MASLD do neither represent a polygenetic background nor the metabolic changes in this population. Therefore, we investigated two new mouse models for MASLD with the polygenetic background for the metabolic syndrome.

Methods:
TALLYHO/JngJ mice and NONcNZO10/LtJ mice received a high-fat- high-carbohydrate (HF-HC) diet with a surplus of cholesterol diet.

Results:
After sixteen weeks of diet, both strains developed pronounced metabolic syndrome with severe obesity and histological manifestation of steatohepatitis. Subsequently, histological onset of MASH was associated with significantly increased intrahepatic CD8+cells, CD4+cells and Tregs, contributing to significant increase of pro-inflammatory and pro-fibrotic gene activation as well as ER stress and oxidative stress. Comparing with human transcriptomic signature, we could proof a good metabolic resemblance in particular for TH mouse model. Moreover, TH mice also developed sings of kidney injury as an extrahepatic comorbidity of MASLD.

Conclusion:
Overall, we developed two promising new mouse models, which are suitable for preclinical investigations of MASLD as they recapitulate most important hallmarks of MASLD.