We have previously reported that high fat diet in combination with diabetes exacerbates NASH progression. Both dietary composition (ie lipid, cholesterol and fructose content) and Type 2 diabetes are risk factors for worsening of NASH but the effect of dietary composition in combination with diabetes on NASH progression has not been studied in this model. The aim of this work was to examine the effect of various diets on NASH progression in a mouse model of dietary induced obesity.

C57BL/6 male mice were fed either a high fat diet (HF:45%kCal fat and 0.2% cholesterol), HF diet containing additional cholesterol (HF+C:2%) or standard chow (CHOW:12%kCal fat), some animals from each group also consumed fructose (F: 5% in drinking water). At 15 weeks of feeding half the animals in each group were rendered diabetic (DM: STZ, 65mg/kg, 3 doses). After a further 10 weeks animals were terminated and their livers were obtained for NASH phenotype assessment by collagen (Sirius red staining) and the fibrosis markers:- profibrotic CTGF and TIMP-1 mRNAs by qPCR.

At 25 weeks, all animals fed a HF diet were heavier than CHOW (by approx 25%, P<0.001) this difference was abolished by diabetes. Compared with CHOW, the PSR staining showed that  HF diet combined with either C or C+F increased liver collagen this was further exacerbated by DM (2 fold, P<0.05 vs CHOW). HF diet+C+DM had the greatest effect (4 fold, P<0.05 vs HF diet+DM). Across all dietary groups the combination of HF diet and DM increased CTGF and TIMP-1 mRNA (by 2 and 4 fold respectively, P<0.05) the greatest increases were observed in the HF diet +C+F group. This data suggests that HF diets containing cholesterol and fructose can further exacerbate NASH in diabetes.