Validation of a diet-induced Macaca fascicularis model of non-alcoholic steatohepatitis with dietary and pioglitazone interventions.

Abstract

To develop an obese, insulin-resistant cynomolgus monkey model of non-alcoholic steatohepatitis (NASH) with fibrosis with a high fat/high cholesterol (HFHC) diet (with or without high fructose) and test its responsiveness to caloric restriction or pioglitazone. First, two groups of monkeys (n=24/group) with histologically proven NASH and fibrosis were fed the HFHC diet for 17 weeks. The treatment group was subjected to a 40% caloric restriction (CR) and had their diet switched from the HFHC diet to a chow diet (DSCR). Paired liver biopsies were taken before and 17 weeks after DSCR. Subsets of monkeys (nine/group) had whole liver fat content assessed by MRI. Next, two groups of monkeys with histologically proven NASH and fibrosis were treated with vehicle (n=9) or pioglitazone (n=20) over 24 weeks. The HFHC and DSCR groups lost 0.9% and 11.4% of body weight, respectively. After 17 weeks, non-alcoholic fatty liver disease activity score (NAS) improvement was observed in 66.7% of the DSCR group versus 12.5% of the HFHC group (P< .001). Hepatic fat was reduced to 5.2% in the DSCR group versus 23.0% in the HFHC group (P= .0001). After 24 weeks, NAS improvement was seen in 30% of the pioglitazone group versus 0% of the vehicle group (P= .08). Both weight loss induced by DSCR and treatment with pioglitazone improve the histological features of NASH in a diet-induced cynomolgus monkey model. This model provides a translational preclinical model for testing novel NASH therapies.