Experimental models of non-alcoholic steatohepatitis (NASH) are still required for understanding pathophysiology of NASH. This study aimed to examine whether disease progression is accelerated by combining dyslipidemic genetic modification and dietary challenges and develop NASH-associated hepatic fibrosis, cirrhosis, and carcinoma in a short period.
Low-density lipoprotein receptor knockout (LDLR-/-) mouse was fed with choline-deficient amino acid-defined (CDAA) diet including 1 w/w% cholesterol and 41 kcal% fat, a modified CDAA (mCDAA) diet, was comprehensively profiled over 1 year.
Microvesicular and macrovesicular steatosis in the liver was observed from 1(st) week after the start of mCDAA-feeding. Macrovesicular steatosis was exacerbated with time and was observed in almost all hepatocytes at 8(th) week, but slightly decreased at 16(th) week. Infiltration of macrophages and neutrophils, and up-regulation of hepatic inflammatory cytokines such as TNF-α and IL-1β were also observed from 1(st) week. Plasma hepatic transaminase activities were increased at 1(st) week, reached a peak at 4(th) week, and gradually decreased thereafter. In parallel with increases in hepatic gene expression of collagen-I, hepatic fibrosis area were expanded after 4(th) week and massively spread all over the liver by 8(th) week. Hepatocellular hyperplasia was observed from 24(th) week. Hepatocellular adenoma and carcinoma were observed from 31(st) and 39(th) week, respectively.
These results suggest that in a rodent NASH model with combination of genetic modification and dietary challenges, following hepatic steatosis, inflammatory cell infiltration and hepatic injury, hepatic fibrosis, hepatocellular hyperplasia, adenoma, and carcinoma can be developed in a relatively short period. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.

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