What is MASH (formerly NASH)?

Recent reports indicate that Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and Metabolic Dysfunction-Associated Steatohepatitis (MASH) are emerging public health threats. MASLD is a common chronic liver disease, with estimates of incidence around 25% worldwide. MASH represents the more severe end of the MASLD spectrum, with inflammation and fibrosis which can progress to cirrhosis and even liver cancer.

According to Younossi et al., "MASLD is one of the most important causes of liver disease worldwide and will probably emerge as the leading cause of end-stage liver disease in the coming decades, with the disease affecting both adults and children¹".

The Silent MASLD Epidemic

MASLD has been compared to a silent epidemic, and incidence is increasing. "MASLD is known to be highly associated with several metabolic conditions...Thus, it is expected that the incidence of MASLD should rise in parallel to the increasing incidence of obesity and "[type 2 diabetes mellitus]"¹."

There are few symptoms until disease is quite advanced. According to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), "Usually, Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and Metabolic Dysfunction-Associated Steatohepatitis (MASH) are silent diseases with few or no symptoms. You may not have symptoms even if you develop cirrhosis due to MASH".

How MASH is Diagnosed

The gold standard for MASH diagnosis is a liver biopsy. Liver enzymes are sometimes normal in people with MASLD. While ultrasound can detect fatty liver, it cannot detect fibrosis or inflammation².

No Approved MASH drugs

There are currently no approved therapeutics for MASLD, so treatment focuses on weight loss and lifestyle changes. Advanced liver disease may require a liver transplant. With a large and growing patient population and no approved therapeutics, pharma and biotech are investing heavily in MASLD/MASH research.

Therapeutic goals are segmented based on different aspects of the disease, such as reducing inflammation, reversing fibrosis, or stabilizing cirrhotic patients. Preclinical research is also thus segmented, with different animal models used depending on the particular MASLD phenotype under investigation.

MASLD/MASH Animal Models

Preclinical animal models for MASLD and MASH can be divided into three classes: diet-induced models, chemically-induced models, and genetic models.

Diet-induced MASLD models

Mice fed a diet deficient in methionine and choline develop hepatic fat accumulation, inflammation and fibrosis, but do not become obese and thus do not represent all aspects of systemic MASLD disease. Diets with various combinations of high fat, high fructose and/or high cholesterol have been widely used to model MASLD. For example, diet-induced obese C57BL/6 mice readily develop steatosis, but do not appear to develop more advanced MASH phenotypes.

The Amylin liver MASH model (AMLN) combines high fat, high fructose and high cholesterol in a single diet. C57BL/6 mice fed the AMLN diet become obese, get fatty liver and develop liver inflammation and fibrosis after 26+ weeks on diet, with inter-animal variability observed for development of the inflammation and fibrosis phenotype^3,4.

One challenge with diet models can be prolonged conditioning time required prior to start of studies. Availability of pre-conditioned mice from animal vendors can dramatically accelerate the start of MASH studies.

Chemically-induced MASLD models

Low dose streptozotocin administration, combined with a high fat diet, has been used to model MASLD in mice, with steatosis, inflammation, fibrosis and even hepatocellular carcinoma resulting. Administration of carbon tetrachloride (CCl₄) is commonly used to induce liver fibrosis, alone or with co-administration of high fat diet³.

Genetic models

Ob/ob mice develop obesity and steatosis, but require additional conditioning in the form of diet or chemical induction to progress on to MASH phenotypes³. Apoe knockout mice, which are commonly used for atherosclerosis research, can develop MASH phenotypes such as steatosis, inflammation and fibrosis when fed a high fat, high cholesterol diet⁵.

Although genetic and chemically-induced models may not be relevant in terms of the mechanism of disease induction, their advantage can be more rapid disease induction. High fat diet models are typically slower, but may better model the full spectrum of MASLD and co-morbid metabolic disease. This list of models is by no means exhaustive and review articles may be consulted for additional information.

Watch the Taconic Biosciences' Webinar:

• The Diet Induced MASH B6: A Translational MASH Model for Drug Discovery

Read the Related Taconic Biosciences' Insights:

• Webinar Q&A -- Using Diet-Induced Obese Mice to Study Metabolic Disease
• Selecting Translatable MASH Animal Models

References:

1. Younossi, Z.; Anstee, Q. M.; Marietti, M.; Hardy, T.; Henry, L.; Eslam, M.; George, J.; Bugianesi, E. Nature Reviews Gastroenterology & Hepatology 2017, 15 (1), 11-20.

2. Nonalcoholic Fatty Liver Disease & MASH: National Institute of Diabetes and Digestive and Kidney Diseases.

3. Herck, M. V.; Vonghia, L.; Francque, S. Nutrients 2017, 9 (10), 1072.

4. Trevaskis, J. L.; Griffin, P. S.; Wittmer, C.; Neuschwander-Tetri, B. A.; Brunt, E. M.; Dolman, C. S.; Erickson, M. R.; Napora, J.; Parkes, D. G.; Roth, J. D. American Journal of Physiology-Gastrointestinal and Liver Physiology 2012, 302 (8).

5. Schierwagen, R.; Maybüchen, L.; Zimmer, S.; Hittatiya, K.; Bäck, C.; Klein, S.; Uschner, F. E.; Reul, W.; Boor, P.; Nickenig, G.; Strassburg, C. P.; Trautwein, C.; Plat, J.; Lütjohann, D.; Sauerbruch, T.; Tacke, F.; Trebicka, J. Scientific Reports 2015, 5 (1).