Animal models of non-alcoholic fatty liver disease: current perspectives and recent advances

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a continuous spectrum of diseases characterized by excessive lipid accumulation in hepatocytes. NAFLD progresses from simple liver steatosis to non-alcoholic steatohepatitis and, in more severe cases, to liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Because of its growing worldwide prevalence, various animal models that mirror both the histopathology and the pathophysiology of each stage of human NAFLD have been developed. The selection of appropriate animal models continues to be one of the key questions faced in this field. This review presents a critical analysis of the histopathology and pathogenesis of NAFLD, the most frequently used and recently developed animal models for each stage of NAFLD and NAFLD-induced HCC, the main mechanisms involved in the experimental pathogenesis of NAFLD in different animal models, and a brief summary of recent therapeutic targets found by the use of animal models. Integrating the data from human disease with those from animal studies indicates that, although current animal models provide critical guidance in understanding specific stages of NAFLD pathogenesis and progression, further research is necessary to develop more accurate models that better mimic the disease spectrum, in order to provide both increased mechanistic understanding and identification/testing of novel therapeutic approaches. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Keywords: animal model; disease histopathology; hepatocellular carcinoma; non-alcoholic fatty liver disease (NAFLD); non-alcoholic steatohepatitis.

Figure 1

The main mechanisms involved in the experimental pathogenesis of NAFLD and NASH in different animal models. In NAFLD, the mechanisms include increased de novo lipogenesis, increased adipose tissue lipolysis, increased dietary FFA levels, impaired β‐oxidation, and impaired VLDL synthesis. These all lead to hepatic triglyceride accumulation and ultimately NAFLD. db/db mice and ob/ob mice develop NAFLD because of both increased de novo lipogenesis and IR, whereas mice fed an HFD develop NAFLD because of increased dietary FFA levels. In NASH, the two main mechanisms for progression of steatosis to steatohepatitis are increased oxidative stress and proinflammatory cytokines. Mice fed an MCD diet develop NASH because of increased oxidative stress; mice fed a high‐cholesterol diet develop NASH because of both increased oxidative stress and proinflammatory cytokines; foz/foz mice develop NASH because of obesity‐induced IR.

Figure 2

Histopathological features of NAFLD in different animal models. (A–C) Representative haematoxylin and eosin (H&E) staining of liver sections of: (A) C57BL/6 mice fed a control diet or an HFD for 12 weeks; (B) db/db and dbm control mice fed normal chow for 6 weeks; and (C) C57BL/6 mice fed a control diet or an MCD diet for 2 weeks. (D) Representative Sirius Red staining of liver sections of C57BL/6 mice fed a control diet or an MCD diet for 8 weeks. (E) Representative H&E staining of liver sections of C57BL/6 mice fed a control diet, an HFHC diet or a CD‐HFD for 12 weeks.