Evolution of MASH Models: Beyond Simple Steatosis

Introduction: From NASH to MASH, Background of the Paradigm Shift

In 2023, a consensus conference led by major international liver societies, including the American Association for the Study of Liver Diseases (AASLD), the European Association for the Study of the Liver (EASL), and the Latin American Association for the Study of the Liver (ALEH), officially decided to change the nomenclature from "Nonalcoholic Steatohepatitis (NASH)" to "Metabolic dysfunction-associated steatohepatitis (MASH)" (Rinella et al., Hepatology 2023).

This change is not merely nominal but explicitly positions "Metabolic dysfunction" within the disease definition. Consequently, in research, there is an increasing emphasis on animal models that more closely mimic human pathology—not just hepatic fat accumulation, but systemic metabolic abnormalities such as insulin resistance and dyslipidemia.

Challenges in Research: Limitations of Traditional Diet-Induced Models

The biggest challenge many researchers face in MASH research is the reproduction of fibrosis.

Excessive Time Required: With standard High-Fat Diet (HFD) or Western Diet alone, it often takes 20 weeks to over 6 months to develop the "ballooning" and "fibrosis" characteristic of human MASH.
Mild Fibrosis: Even after long-term feeding, the resulting fibrosis often remains mild (F1-F2), which may be insufficient for evaluating the efficacy of anti-fibrotic drugs.
Variability and Reproducibility: Diet-induced models show significant inter-individual variability, requiring large sample sizes (N) to achieve statistical significance, thereby increasing research costs and time.

As discussed in top journals like Nature Reviews Gastroenterology & Hepatology, an ideal MASH model must possess both metabolic abnormalities (obesity, insulin resistance) and histological features (steatosis, inflammation, fibrosis). Achieving this with a single model in a short timeframe is not easy.

Solution: Accelerated MASH Models and Quantitative Assessment

To address these challenges, "Accelerated MASH Models" are gaining attention.

1. Shortening Duration via Combined Approaches

By combining dietary loading with low doses of chemical agents (e.g., CCl4) or using specific diet compositions (e.g., Choline-Deficient L-Amino Acid-defined diet: CDAA), it is possible to induce severe fibrosis (F3-F4) within a short period of 8-12 weeks while maintaining metabolic abnormalities. This dramatically shortens the drug discovery screening cycle.

2. Objective Fibrosis Quantification

While scoring by a pathologist remains the gold standard, automated quantification of "Collagen Proportion Area (%)" using Sirius Red-stained sections and image analysis is recommended to eliminate inter-observer bias. This allows for the numerical detection of subtle differences in drug efficacy.

Conclusion

As competition in MASH drug development intensifies, appropriate model selection is a critical key to research success. Our partner CRO offers diverse MASH models based on the latest consensus (diet-induced, chemical combination, genetic modification) along with advanced fibrosis evaluation systems.

If you are a researcher struggling with "not knowing the best model for your compound" or "lacking time to set up a fibrosis evaluation system," please feel free to consult us.

References

Rinella ME, et al. A multi-society Delphi consensus statement on new fatty liver disease nomenclature. Hepatology. 2023;78(6):1966-1986.
Friedman SL, et al. Mechanisms of NAFLD development and therapeutic strategies. Nat Med. 2018;24(7):908-922.