Abstract
ABSTRACTNon-alcoholic steatohepatitis (NASH) is a fast-growing liver disease in the Western world. Currently, only a few animal models show both the metabolic and histological features of human NASH. We aimed to explore murine NASH models in a time dependent manner that exhibit metabolic, histological and transcriptomic hallmarks of human NASH. For this, the murine strains C57BL/6J, ob/ob, and KK-Ay were used and three types of nutritional regimes were administered: normal chow diet (NCD); high-fat, high-fructose, and high-cholesterol diet (fast food diet; FFD); or choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD), for 2, 4, 8, 12, 18, 24, and 30 weeks. All strains under the FFD and CDAHFD regimes developed steatohepatitis. Among the strains treated with FFD, the non-alcoholic fatty liver disease (NAFLD) activity score, fibrosis progression and metabolic abnormalities such as hyperinsulinemia and obesity were more pronounced in ob/ob mice than in C57BL/6J and KK-Ay mice. In ob/ob mice fed FFD, the development of hepatic crown-like structures was confirmed. Furthermore, molecular pathways involved in steatohepatitis and fibrosis showed significant changes from as early as 2 weeks of starting the FFD regime. Ob/ob mice fed FFD showed metabolic, histological, and transcriptomic dysfunctions similar to human NASH, suggesting their potential as an experimental model to discover novel drugs for NASH.
Highlights
The number of patients with non-alcoholic steatohepatitis (NASH) has dramatically increased with the increase in the prevalence of obesity, type-2 diabetes and metabolic syndrome (Angulo, 2002; Sanyal, 2011; Saponaro et al, 2015)
All strains administered FFD developed obesity compared with those fed normal chow diet (NCD) and CDAHFD The C57BL/6J, ob/ob and KK-Ay mice fed FFD all gained more body weight than mice on the NCD regime, and developed obesity (Fig. 1A–C)
FFD-fed ob/ob mice showed metabolic hallmarks of human NASH The FFD regime significantly increased plasma insulin levels in C57BL/6J mice compared with the NCD regime at 12 and 18 weeks (Fig. 2A)
Summary
The number of patients with non-alcoholic steatohepatitis (NASH) has dramatically increased with the increase in the prevalence of obesity, type-2 diabetes and metabolic syndrome (Angulo, 2002; Sanyal, 2011; Saponaro et al, 2015). NASH is a growing cause of hepatocellular carcinoma (HCC) and liver transplantation, and its therapeutic management is increasingly important for preventing. In patients with NAFLD, diabetes is an independent predictor of moderate-to-severe fibrosis (Hossain et al, 2009). These findings highlight the importance of obesity, hyperinsulinemia, and diabetes in NASH progression
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