A novel non-alcoholic steatohepatitis animal model featured with insulin resistance, hepatic inflammation and fibrosis

Abstract

Objective. There is no animal model that displays the features of non-alcoholic steatohepatitis (NASH) characterized by insulin resistance (IR) and fibrosing steatohepatitis. This study aimed to develop a novel IR-associated rat model of NASH. Material and methods. Male Sprague–Dawley rats were fed with the high-fat diet (HFD) supplemented with 0.25% propylthiouracil for 2, 4, 6, 8 and 12 weeks. The IR-associated metabolic parameters, histological assessment and the expression of key insulin signaling molecules were determined. The circulating and tissue pro-inflammatory factors and adipocytokines were examined. Results. In the HFD-fed rats, the systemic and multiple-organ IR was developed after 4 weeks, whereas the histological changes characterized by steatohepatitis, inflammatory response in the visceral adipose tissue and proliferative pancreatic islet β-cells appeared after 6 weeks, concomitant with altered expression of key insulin signaling molecules. In addition, the elevated levels of serum tumor necrosis factor α (TNF-α), soluble TNF receptor2, interleukin (IL)-6, CC-chemokine ligand (CCL)2 and resistin were parallel with the severity of hepatic inflammation, while the levels of serum adiponectin, leptin and TNF-α, but not resistin, were correlated with IR. Conclusions . We have developed a systemic IR-associated NASH model of rats, with impaired insulin signaling, systemic inflammation and appropriate pathology characterized by human NASH, and provided a realistic experimental model for elucidating the association between IR and the pathogenesis of NASH.

Key Words::

• High-fat diet
• inflammation
• insulin resistance
• model of non-alcoholic steatohepatitis
• propylthiouracil

Acknowledgements

The authors wish to thank Jianfa Yang, Deng Pan and Yanling Sun for their excellent technical assistance; Xiaodong Guo and Suxian Zhao for animal care.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing the paper.