Targeting non-alcoholic steatohepatitis induced by high fat feeding and type 2 diabetes in a preclinical model

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the developed world and it is strongly associated with metabolic derangements, such as insulin resistance, dyslipidaemia, obesity and hyperglycaemia. The prevalence of NAFLD is estimated to be up to 80% in patients with obesity or type 2 diabetes compared with 20-30% in the general adult population, reflecting that both obesity and type 2 diabetes cosegregate with NAFLD. In particular, type 2 diabetes is an independent risk factor for NAFLD progression. However despite the commonality of NAFLD, and its potential to progress to cirrhosis and hepatoma, there is no specific treatment targeting NAFLD. In this context it is thus important to examine whether current novel therapies, such as anti-diabetic agents and molecular interventions, can prevent NAFLD progression, especially the severe change of liver fibrosis. Amongst the series of classes of agents used commonly clinically to treat type 2 diabetes, the biguanide, metformin, and the thiazolidinedione, pioglitazone, have each been shown in rodent models and in human NAFLD to prevent human NAFLD progression, albeit in some histopathological aspects of NASH. Amongst two other commonly used class of agent clinically, the sulphonylureas (SU), and the dipeptidyl dipeptidase inhibitors (DPP4i), have been minimally studied. In particular, remarkably there is no human or animal data for use of SU in NASH, and only limited rodent data, without fibrosis end-points, for the potential utility and mechanism(s) of action for DPP4i in NASH. The initial chapters in this thesis thus examined the efficacy and potential mechanisms(s) of action of the most commonly used SU clinically in Australia, gliclazide, and the most commonly prescribed DPP4i used in Australia, sitagliptin, in rodent models of NASH, including in the presence and absence of vii type 2 diabetes