Abstract
BackgroundNon-alcoholic fatty liver disease (NAFLD) is defined as a spectrum of conditions ranging from hepatocellular steatosis to steatohepatitis and fibrosis, progressing to cirrhosis, which occur in the absence of excessive alcohol use. Several animal models capture aspects of NAFLD but are limited either in their representation of the disease stages or use for development of therapeutics due to the extended periods of time required to develop full histological features.MethodsHere, we report the development of a novel rat model for NAFLD that addresses some of these limitations. We used a fast food diet (FFD) and a CCl4 micro dose (0.5 ml/kg B.wt) for 8 weeks in Wistar rats. Serological analyses, gene expression profiling and liver histology studies were conducted to investigate the development of steatosis, steatohepatitis and fibrosis in the FFD-CCl4 model when compared to the individual effects of a FFD or a micro dose of CCl4 in rats.ResultsThe serum biochemical profile of the FFD-CCl4 model showed an increase in liver injury and fibrosis. This was also accompanied by a significant increase in liver triglycerides (TG), inflammation and oxidative stress. Importantly, we observed extensive fibrosis confirmed by: i) increased gene expression of fibrosis markers and, ii) moderate to severe collagen deposition seen as perisinusoidal and bridging fibrosis using H&E, Trichome and Sirius Red staining.ConclusionsIn summary, we find that the FFD-CCl4 rat model developed NAFLD histological features including, steatosis, inflammation and fibrosis in 8 weeks showing promise as a model that can be used to develop NAFLD therapeutics and liver anti-fibrotics.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is defined as a spectrum of conditions ranging from hepatocellular steatosis to steatohepatitis and fibrosis, progressing to cirrhosis, which occur in the absence of excessive alcohol use
The serum biochemical profile of the fast food diet mouse model (FFD)-Carbon Tetrachloride (CCl4) model showed an increase in liver injury and fibrosis when compared to FFD alone, CCl4 alone or the chow diet control animals along with significant increase in liver TG, inflammation and oxidative stress in the FFD-CCl4 model
Alanine transaminase (ALT), Aspartate transaminase (AST), Gamma-glutamyl transpeptidase (GGT) and Alkaline phosphatase (ALP) and procollagen type III were significantly elevated in the FFD-CCl4 animals compared to the chow diet controls (Table 3)
Summary
Non-alcoholic fatty liver disease (NAFLD) is defined as a spectrum of conditions ranging from hepatocellular steatosis to steatohepatitis and fibrosis, progressing to cirrhosis, which occur in the absence of excessive alcohol use. Non-alcoholic fatty liver disease (NAFLD) is defined by a spectrum of conditions that occur in the absence of excessive alcohol use and range from hepatocellular steatosis to steatohepatitis (NASH) and fibrosis, progressing to cirrhosis [1,2]. Research efforts in NAFLD have been aimed at understanding disease development, progression and pathophysiology simultaneously facilitating drug discovery. To this end, various animal models of NAFLD have evidence of fibrosis/cirrhosis across routes of CCl4 administration. The model showed significant physiological similarity to human NASH but took 24 weeks to develop all the histological features [20]
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