Characterization of a murine nonalcoholic steatohepatitis model induced by high fat high calorie diet plus fructose and glucose in drinking water

There are varieties of murine models of nonalcoholic steatohepatitis (NASH) with different pathophysiologic characteristics. For preclinical assessment, a standardized model would allow comparisons of various pharmacotherapeutic candidates in efficacy, pharmacokinetics, pharmaco-metabolism, and adverse effects under a same system. The present study aims to characterize murine NASH models by comparing end-points of major abnormalities. NASH was induced by feeding high fructose/glucose in drinking water (HF/G), high-fat/calorie diet (HFCD), and in combination (HFCD-HF/G) in mice for 8 or 16 weeks. HF/G feeding caused a minimal fat accumulation and increase in free fatty acids (FFA). In contrast, HFCD-HF/G feeding resulted in a remarkable increase in body weight, subcutaneous and visceral adipose tissue, macrosteatosis with a nearly seven-fold increase in triglyceride and FFA content, accompanied with marked hepatocellular injury, inflammatory responses, fibrosis, and insulin resistance, and represented as typical NASH in histopathology, metabolic, and adipokine profiles in a progressive manner. Meanwhile, mice fed HFCD displayed significant steatosis, necroptosis, fibrosis, insulin resistance, metabolic, and adipokine profiles, and the extent is less than those fed HFCD-HF/G. Significant MCP-1, CCR-2, and NLRP-1/3 activation were found in mice fed HFCD and HFCD-HF/G for 16 weeks, whereas gene expression of CPT-1 and ACOX-1 was down-regulated in these two groups in comparison to the controls. Nuclear receptors, such as SREBP-1c, FXR, LXR-α, PPAR-α, and PPAR-γ, were strikingly elevated in the HFCD-HF/G group. In conclusion, feeding HFCD-HF/G resulted in a reliable NASH model in mice with remarkable necroptosis, steatosis, fibrosis, and insulin resistance as well as a disordered profile of lipid metabolism and adipokine, and HFCD caused significant NASH features in histopathology and metabolic profiles only at a late stage. Whereas HF/G feeding barely led to minimal fat accumulation, some changes at molecular levels and metabolic disturbance in mice. Providing a high fat/calorie diet plus high fructose/glucose in drinking water is shown to be an optimal approach to induce nonalcoholic steatohepatitis in mice. The animal model shows remarkable necroptosis, steatosis, fibrosis and insulin resistance as well as a disordered profile of lipid metabolism and adipokines. This model should prove useful for pathophysiologic investigation and pharmacologic development.