Nonalcoholic steatohepatitis (NASH) arises from a variable interplay between environmental factors and genetic determinants that cannot be completely replicated in animals. Notwithstanding, preclinical models are needed to understand NASH pathophysiology and test mechanism-based
therapies. Among several mouse models of NASH, some exhibit the key pathophysiologic as well as histopathologic criteria for human NASH, whereas others may be useful to address specific questions. Models based on
overnutrition with adipose restriction/
inflammation and metabolic complications, particularly
insulin resistance, may be most useful to investigate critical etiopathogenic factors. In-depth pathologic description is required for all models. Some models demonstrate hepatocyte ballooning, which can be confused with microvesicular steatosis, whereas demonstration of an inflammatory infiltrate and pattern of
liver fibrosis compatible with human NASH is desirable in models used for pharmacologic testing. When mice with specific genetic strains or mutations that cause
overeating consume a diet enriched with fat, modest amounts of
cholesterol, and/or
simple sugars ("Western diet"), they readily develop
obesity with
liver disease similar to human NASH, including significant
fibrosis. Purely dietary models, such as high-fat/high-
cholesterol, Western diet, and
choline-deficient,
amino acid-defined, are similarly promising. We share concern about using models without
weight gain, adipose pathology, or
insulin resistance/
hyperinsulinemia and with inadequate documentation of liver pathology. NASH-related
fibrosis is a key endpoint in trials of possible
therapies. When studied for this purpose, NASH models should be reproducible and show
steatohepatitis (ideally with ballooning) and at least focal bridging
fibrosis, while metabolic factors/disordered
lipid partitioning should contribute to etiopathogenesis. Because murine models are increasingly used to explore pharmacologic
therapies for NASH, we propose a minimum set of requirements that investigators,
drug companies, and journals should consider to optimize their translational value.