Characterization of a Novel Murine Model For NASH

The growing epidemics of obesity and type 2 diabetes have fueled an increasing prevalence of non-alcoholic fatty liver disease (NAFLD) across the globe, with around one quarter of US adults now affected.¹

 Many believe that NAFLD is yet to be widely recognized as a major public health challenge. For example, several liver disease experts recently wrote in the BMJ Opinion: “It seems implausible that an illness which affects an estimated two billion people globally, causes a substantial burden of ill health, and has wide ranging social and economic implications, still remains as obscure as NAFLD is today.”²

 NAFLD is a silent disease which presents with few or no symptoms in most patients. The condition comprises a spectrum of liver damage that is not caused by alcohol, including nonalcoholic fatty liver (NAFL) or steatosis, which can progress to nonalcoholic steatohepatitis (NASH), cirrhosis, and in some cases hepatocellular carcinoma (HCC).

Despite considerable research in this field, there is currently a lack of understanding around the mechanisms responsible for disease development and progression, and there are no simple tests available for diagnosis. Furthermore, there are no therapeutics approved for treatment of the condition.

Murine NASH Models

A major barrier to the development of therapeutics for NASH is the lack of pre-clinical models of disease that are fully validated to represent the pathophysiology of human disease. Current NASH models are often classified into two major categories: genetic manipulation or nutritional induction.³

• Genetic Manipulation Models – the majority of these models are identified during studies of gene function and are used to characterize impacts of a specific transgene or knockout. While these models are useful for understanding the function of specific genes and associated pathways, they are less relevant to the etiologies and clinical profiles of patients with NASH.
• Nutritional Induction Models – the most commonly used diet-induced NASH models that exist are the methionine/choline-deficient (MCD) diet and high-fat/calorie diet. The high-fat/calorie diet is most often used as it mimics Western fast-food dietary composition; however, since there are many different recipes, feeding combination, and duration, it is hard to establish a reliable model.

Establishing a Standardized NASH Model

It can be difficult for researchers to estimate the efficacy of therapeutic candidates in a preclinical setting when no standardized murine NASH model is available. With this in mind, Professor Jian Wu, who is based at Fudan University Shanghai Medical College in China, and colleagues characterized several murine NASH models by comparing major endpoints such as steatosis, hepatocellular injury, and inflammatory responses.

The team reports that feeding mice a combination of fructose/glucose in drinking water (HF/G) and a high-fat/calorie diet (HFCD) resulted in a reliable model of NASH.³ Writing in Laboratory Investigation the researchers said: “The characterization of a murine NASH model provides a means of standardization in end-point variables and offers a cross-board comparison of pharmacologic candidates in effectiveness and adverse effects.”

To find out more about the team’s work, and the challenges associated with fatty liver diseases, read our exclusive interview with Professor Wu.

References

1. NASH Definition & Prevalence [Internet]. American Liver Foundation. 2021 [cited 11 August 2021]. Available from: https://liverfoundation.org/for-patients/about-the-liver/diseases-of-the-liver/nonalcoholic-steatohepatitis-information-center/nash-definition-prevalence/
2. NAFLD: Putting the spotlight on a hidden public health challenge – The BMJ [Internet]. The BMJ. 2021 [cited 11 August 2021]. Available from: https://blogs.bmj.com/bmj/2021/03/09/nafld-putting-the-spotlight-on-a-hidden-public-health-challenge/
3. Liu X, Duan N, Liu C, Niu C, Liu X, Wu J. Characterization of a murine nonalcoholic steatohepatitis model induced by high fat high calorie diet plus fructose and glucose in drinking water. Laboratory Investigation. 2018;98(9):1184-1199.