Development of a novel mouse model of diet-induced nonalcoholic steatohepatitis-related progressive bridging fibrosis

Abstract

Nonalcoholic steatohepatitis (NASH) progresses to liver fibrosis and cirrhosis. Existing mouse models of NASH rarely develop diet-induced severe fibrosis. We aimed to establish a dietary model of NASH with rapid progression to fibrosis. Six-week-old male Tsumura-Suzuki obese diabetes (TSOD) mice (a model of spontaneous metabolic syndrome) and corresponding control Tsumura-Suzuki nonobese (TSNO) mice were fed a novel diet high in fat, cholesterol, and cholate (iHFC). Histologic steatohepatitis, including steatosis, inflammation, and fibrosis, were observed in both TSNO and TSOD iHFC diet-fed mice at 20 weeks of age. As compared with TSOD mice, TSNO mice developed much more severe fibrosis and reached stage 3 of bridging fibrosis within 14 weeks under the iHFC diet feeding. Perivenular/perisinusoidal pattern of fibrosis in TSNO mice resembled human NASH. Our model of NASH with advanced fibrosis by simple diet offers many advantages useful in studying the mechanism of liver fibrosis and preclinical drug testing.