Investigation of Non-alcoholic steatohepatitis development in newly designed short-term insulin resistance-fatty liver rat models. From chronic to acute

Abstract

Abstract Background The progression of insulin resistance (IR) and diabetes into non-alcoholic steatohepatitis (NASH) is a chronic process. The pathogenesis of diabetes progression into NASH is very complex and not fully understood. The lack of reproducible IR-NASH animal models that mimic human pathogenesis is the main roadblock. Therefore, we designed this study to investigate the development of IR-NASH within one month using new combinations of diets, fructose, and a small dose of streptozotocin (MFD or HFD/HFrD/STZ). And compare them with the known IR-NASH model using HFD/STZ. Methods Thirty-two male Wistar rats were randomized into four different groups and fed by either a different combination of diets or a chow diet for one month. After two weeks, a single dose of STZ was injected in all groups except the healthy group to develop diabetes. Body weights, animal mortality, eating, and drinking behaviors were recorded during the study. Glucose intolerance, hepatotoxicity indices, and fat accumulation were investigated. Also, we examined the hepatic histopathological alternations in rats. Results Animals’ body weights, eating, and drinking behaviors were extremely affected in high fructose diet (HFrD)-feed groups. Also, all groups showed a significant IR and glucose intolerance. However, the clear progressive NASH with aggressive hepatic steatosis, inflammation, and fibrosis was visualized in the investigated liver sections’ of HFrD-feed groups only. At the same time, the HFD/STZ group showed progressive non-alcoholic fatty liver disease (NAFLD) only. Conclusion MFD or HFD/ HFrD/ STZ models were successful short-term NASH models that can be used for pharmacological screening studies and dose selection. While HFD/STZ is a suitable model for chronic pharmacological investigations.