Advance your NASH Therapeutics with a more Translatable Mouse Model of Dysmetabolism and Clinically-Relevant NASH Progression

Many existing NAFLD/NASH models display only the histopathology (e.g. fibrosis) or physiological properties of human NAFLD/NASH, therefore lacking clinical relevance. The MS-NASH (formely called FATZO) mouse represents a more translational model, better recapitulating the complex human disease. MS- NASH Key features:

• Develops NAFLD/NASH in an inherently dysmetabolic, obese, and diabetic mouse model; more closely resembling NAFLD/NASH development in the context of dysmetabolism
• Polygenic model with an intact leptin pathway, as seen in humans
• Elevated liver injury markers (ALT, AST) and liver triglycerides on a “Western” diet
• Accelerated disease progression and exacerbated pathology with CCl₄ administration
• Consistently develops various NAFLD/NASH-associated pathologies: steatosis, hepatocyte ballooning, inflammation, and fibrosis
• OCA treatment improves NAS score and lipid profile

Model Description:

The MS-NASH (formerly called FATZO) mouse model was created by inducing NAFLD/NASH through administration of a “Western diet” plus fructose. On diet, the model develops steatosis, hepatocyte ballooning, inflammation, and fibrosis over time. Progression and exacerbated NASH pathology is accelerated with administration of CCl₄.

Western Diet: 21% fat, 0.2% cholesterol, 5% fructose in drinking water.

MS-NASH Mouse Background:

The MS-NASH mouse is an inbred polygenic animal model for obesity, metabolic syndrome, and diabetes. The model was created through crossing AKR/J and C57BL/6J strains followed by selective inbreeding. Both strains are highly sensitive to developing obesity and metabolic syndrome under the influence of high fat diets, and leptin resistance while gaining adiposity.

The crossing of these two strains and the selective inbreeding of the subsequent generations resulted in the MS-NASH strain, exhibiting obesity in a pre-diabetic state which slowly progresses to overt diabetes.

MS-NASH Phenotype:

• On a Western diet, the MS-NASH mouse model develops elevated body weight, body fat, and liver weight, alongside NAFLD/NASH in an inherent mouse model of type 2 diabetes
• Elevated serum markers of liver injury (ALT, AST) and elevated liver triglycerides
• Develops NAFLD/NASH-associated pathologies on a Western Diet: steatosis (by 4-8 weeks), hepatocyte ballooning and inflammation (by 16 weeks), NASH and fibrosis (by 20 weeks)
• Accelerated and exacerbated pathologies observed on Western diet + CCl₄:
  • Steatosis by 4 weeks
  • Hepatocyte ballooning by 4-8 weeks
  • Inflammation by 8-16 weeks
  • Fibrosis in as little as 12 weeks, exacerbated from mild or moderate (fibrosis score ~1.5 at 20 weeks) towards severe (fibrosis score >2.5 at 12-16 weeks)

Table 1: Summary of NAFLD/NASH progression in MS-NASH Mouse on Western diet and accelerated Western diet + CCl₄

MS-NASH Model Develops NAFLD Progressing into NASH
by 20 Weeks on a Western Diet

Figure 1: Scoring for progression of NAFLD/NASH pathologies in individual mice. Each dot represents an individual mouse in a cohort, either on a standard diet (blue) or on western diet (orange).

Development of Fibrosis by 20 weeks in MS-NASH Model (Picosirius Red Staining)

Figure 2: Progression of fibrosis in MS-NASH model (Picosirius red staining). Arrows mark fibrotic processes.

MS-NASH Model Shows Improved NAS Score with OCA Treatment

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Figure 3: OCA treatment improves hepatic ballooning in MS-NASH mice. Representative images of H&E and PSR staining of livers from MS-NASH mice treated with OCA or vehicle	Figure 4: Histological improvement of WDF fed MS-NASH mice treated with OCA (A) hepatic ballooning, (B) steatosis, (C) lobular inflammation, (D) fibrosis, and (E) NAS score

CCl₄ Induction MS-NASH Liver Histology Scoring

Figure 5: Liver NAS and fibrosis scoring of MS-NASH mice under different diets and treatments, including CCl₄ (purple) and CCl₄ + OCA (light blue). OCA reduced steatosis and fibrosis in MS-NASH mice.

Resources:

• Presentation: Utility of an Accelerated Translational Model of NASH: MS-NASH Mouse Induced with High Fat Diet and CCl₄
  
  
• Poster: The FATZO Mouse Fed a Western Diet + 5% Fructose Develops NAFLD and NASH
  
  
• Publication: The FATZO mouse, a next generation model of type 2 diabetes, develops NAFLD and NASH when fed a Western diet supplemented with fructose