Mouse models of nonalcoholic steatohepatitis and their application to new drug development

Abstract

Nonalcoholic steatohepatitis (NASH) is one of the important liver diseases currently attracting attention in liver research and drug development. Appropriate mouse models should be used to identify the mechanisms underlying the pathogenesis and progression of NASH in humans and to evaluate the efficacy of anti-NASH agents under development to treat this disease. In this review, we first summarised recent histopathology and pathogenesis of NASH in humans, including the concept of resolution of inflammation. We also examined whether these characteristics of NASH in humans are adequately reflected in mouse models. Through this review, we identified the usefulness and limitations of mouse models widely used in research on NASH. Mouse models can be divided into three main types: diet models, chemical models using toxic compounds, and genetic models using genetically transgenic mice. Genotype models are likely suitable for evaluating anti-NASH compounds because fibrosis, which is considered an important index to determine the drug efficacy of NASH inhibitors, is rapidly induced in genetic models. Using these models, we introduced some selected cases of NASH inhibitor development. This review aims to enhance the understanding of the pathogenesis of NASH and provide a basis for successfully selecting and utilising appropriate animal models of NASH in the development of effective inhibitors.