Su1958 A Novel Murine Model Recapitulates the Pathogenesis of Human Non-Alcoholic Steatohepatitis (NASH) and NASH-Related Hepatocellular Carcinoma

Abstract

Non-alcoholic steatohepatitis (NASH) is a pathological liver condition that occurs in the absence of alcohol abuse and is characterized histologically by steatosis, lobular inflammation, hepatocyte ballooning and fibrosis. NASH is a progressive disease that can lead to hepatocellular carcinoma (HCC), and there is a growing need in the therapeutic field for a reliable and clinically relevant model system that recapitulates the natural history of NASH and encompasses hallmark changes in gene expression, cellular dynamics and metabolic parameters. We have developed a novel NASH mice model (STAMTM) by neonatal low-dose streptozotocin injection to induce a diabetic state in mice and high-fat diet feeding to develop steatosis and mild chronic hepatic inflammation from 4 weeks of age onwards. The STAMTM model reproduced the pathological course of NASH, with step-wise disease progression from simple steatosis to HCC in a relatively short time (NASH and HCC were evident at 8 and 18 weeks after birth, respectively). It showed typical features of human NASH especially as indicated by the following. 1) Histopathology: microand macro-vesicular fat deposition, inflammatory cell infiltration, hepatocyte ballooning and fibrosis, with NAFLD Activity score of 5 at 8 weeks of age. 2) Hepatic gene expression profiles: up-regulation of TNF-α, TGFβ, MCP-1, TIMP-1, α-SMA and collagen Type 1 and 3. In the STAMTM mice, steatohepatitis with lobular fibrosis was evident at 8 weeks of age, which was much earlier than conventional animal models. Furthermore, almost all STAMTM mice developed HCC, with macroscopic appearance of tumor nodules observed at 18 weeks of age on average. These characteristics, together with reproducibility of the disease onset and regularity of the progression, endow the STAMTM model with advantages as a useful preclinical NASH model. Body weight, fasting blood sugar, serum AST, serum ALT, Liver TG, NAS