(A) mouse model for metabolic stress-induced nonalcoholic fatty liver disease and subsequent hepatocellular carcinoma

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a rapidly growing metabolic disease that presents with a wide range of clinical manifestations from fatty liver to hepatocellular carcinoma (HCC). However, there are limitations in NAFLD research due to lack of appropriate animal models that reflects the full range of the disease with physiological relevance. In this thesis, I generate NAFLD model accompanied with diabetes by injecting low dose streptozotocin to male C57Bl/6J mice from 7 weeks of age and then fed them high fat diet (HFD) from 8 weeks of age.The model mice developed similar physiological features of human NAFLD including hyperglycemia, obesity, dyslipidemia, and adipose tissue inflammation. They also sequentially developed hepatic steatosis, steatohepatitis, progressive hepatic fibrosis, and HCC at 14, 20, 32, and 38 weeks of age. And discontinuation of HFD feeding or treatment of Glucagon-like peptide 1 receptor agonists suppressed progression of the disease. Transcriptomics and epigenomics studies revealed that the model mice liver showed sequential change as NAFLD progresses. In detail, expression of DNA damage response and mitotic cell cycle proliferation related genes were epigenetically downregulated in the model mice liver at 20 weeks of age. Furthermore, substantial association between the model mice and human NAFLD patients with similar liver histology was observed in overall gene expression alterations at transcriptome level. In short, we have developed a novel and easily manageable mouse model of NAFLD and subsequent NAFLD-related HCC. This model mimics physiological, metabolic, histological and transcriptomic alterations that occur in human patients as NAFLD progresses.