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The CD model of NASH and fibrosis

Non-alcoholic liver disease, or NASH, is the manifestation of metabolic disorder in the liver. The symptoms are often silent resulting in patients being unaware of their condition until the later stages of the disease. When NASH is associated with scarring in the liver, known as fibrosis, the propensity for the development of hepatic carcinoma and ultimately end-stage liver disease is high. As there are currently no approved therapies for the treatment of NASH and fibrosis this is an area of high-unmet therapeutic need.

At Sygnature Discovery we offer the gold standard choline deficient diet mouse model of NASH and fibrosis, the CD mouse. This model was developed as a refinement of the methionine and choline deficient (MCD) diet mouse. The MCD mouse is a good model of NASH and fibrosis but has the disadvantage of inducing ~40% weight loss over 6 weeks. Although the CD mouse induces some degree of weight loss (~15%) which contrasts with the typical clinical presentation of the disease this smaller reduction in body weight allows the assessment of NASH and fibrosis treatments which also produce reductions in bodyweight. As NASH and fibrosis typically develops in obese patients, the ability to assess compounds for not only their anti-NASH and anti-fibrosis potential but also their ability to induce weight loss is a clear advantage of the  CD mouse.

 

Mice are maintained on the CD diet for 6 weeks. Resulting in increases in the following parameters:

  • Plasma levels of liver enzymes (ALT and AST)
  • Liver collagen and lipids
  • Histological endpoints of NASH (i.e. steatosis, hepatocellular ballooning and lobular inflammation) and fibrosis

 

Our CD mouse model has been validated with the peroxisome proliferator activated receptor (PPAR) gamma agonist, pioglitazone, and the dual PPAR alpha/delta agonist, elafibranor. Pioglitazone  has demonstrated efficacy for the long-term treatment of NASH in patients with prediabetes or type 2 diabetes  and reduces or inhibits many of the features of NASH and fibrosis in the CD mouse.

Pioglitazone and elafibranor improve histological endpoints of NASH and fibrosis in the CD mouse

Mean and SEM (n=11-13). Significance vs normal diet control are denoted by **p<0.01 and ***p<0.001. Significance vs CD diet control are denoted by †p<0.05, ††p<0.01 and †††p<0.001.
* The NAFLD activity score (NAS) generated by combining scores for # parameters; steatosis, hepatocellular ballooning, and lobular inflammation.

Pioglitazone and elafibranor reduce liver fibrosis in the CD mouse model of NASH and fibrosis

Representative images of sirius red stained liver sections, magnification x10 demonstrating the difference between the vehicle, CD diet, Pioglitazone and Elafibranor groups.