Diet-Induced Mouse Model of Nonalcoholic Steatohepatitis That Replicates the Human Disease

OBJECTIVES: Developing a mouse model of nonalcoholic steatohepatitis (NASH) with obesity and fibrosis. METHODS: We fed agouti yellow male mice, which are hyperphagic, a western diet and water containing high fructose corn syrup for either 16 weeks or a year. We measured body weight and composition; we evaluated the development of NASH by histopathology and analyzed changes in gene expression by RNASeq. RESULTS: After 16 weeks, the mice had higher body weight and fat mass. The mice developed NASH with activity scores 5-6; this was confirmed by higher liver triacylglycerol content, elevated plasma ALT and AST activities, and greater hepatic infiltration by CD45-expressing leukocytes. The mice developed liver fibrosis, which was stage 1 after 16 weeks, and stage 3 after a year. Liver gene expression analysis showed increases in lipogenesis-, inflammation-, and fibrosis-related genes. Gene set enrichment analysis showed that 90% of the pathways were similarly upregulated or downregulated in the livers of mice and in human patients with NASH. CONCLUSIONS: In this mouse model, NASH is induced with a diet similar to the average US diet, without nutritional deficiencies or hepatotoxins. NASH replicates the human disease, including the development of advanced fibrosis and very similar changes in gene expression. These similarities make this model useful for the study the pathophysiology of NASH and for preclinical studies of new drugs. FUNDING SOURCES: NIH, NSFC.