Preclinical models of non-alcoholic fatty liver disease

Abstract

Non-alcoholic fatty liver disease (NAFLD) can manifest as non-alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH). NASH is often associated with progressive fibrosis which can lead to cirrhosis and hepatocellular carcinoma (HCC). NASH is increasing as an aetiology for end-stage liver disease as well as HCC. There are currently no approved therapies for NASH. A major barrier to development of therapeutics for NASH is the lack of preclinical models of disease that are appropriately validated to represent the biology and outcomes of human disease. Many in vitro and animal models have been developed. In vitro models do not fully capture the hepatic and extrahepatic milieu of human NASH and large animal models are expensive and logistically difficult to use. Therefore, there is considerable interest in the development and validation of mouse models for NAFLD, including NASH. Several models based on varying genetic or dietary manipulations have been developed. However, the majority do not recreate steatohepatitis, strictly defined as the presence of hepatocellular ballooning with or without Mallory-Denk bodies, accompanied by inflammation in the presence of macrovesicular steatosis. Others lack validation against human disease. Herein, we describe the best practices in development of mouse models of NASH. We further review existing models and the literature supporting their use as a surrogate for human disease. Finally, data on models to evaluate protective genes are discussed. It is hoped that this review will provide guidance for the interpretation of data derived from mouse models and also for the development and validation of newer models.

Keywords: Fibrosis; Mouse models; NAFLD activity score; Non-alcoholic fatty liver disease; Non-alcoholic steatohepatitis; Preclinical models; Transcriptome.

Fig. 1

The key features of human NAFLD and representative histological features in a mouse model of NAFLD (DIAMOND). Predominantly macro-vesicular steatosis in steatohepatitis (left panel 10x) after 16 weeks of a high fat diet (Harlan Teklad # TD 88137) with ad libitum administration 23.1g/L d-fructose and n18.9 g/L d-glucose) in the DIAMOND mice. The pattern is similar to that seen in humans with NASH (Panels A and B (right panel 10x)). Similarly, Panels C and D demonstrate hepatocellular ballooning in mice and in humans respectively. Panels E and F demonstrate lobular inflammation in mice and in humans. These provide proof of concept that the features of human NASH can be recapitulated in humans (adapted from asgharpour et al., 7).

Fig. 2

Fibrosis development and progression in a mouse model of steatohepatitis (DIAMOND mouse) and its similarity to human disease. Initially pericellular fibrosis around the central vein is noted followed by both portal and pericellular fibrosis and eventually bridging fibrosis with early nodule formation. Data for mice are shown in the left panels whereas data for humans are shown on the right panel (adapted from asgharpour et al., 7).