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

• Published in: Diabetes, obesity & metabolism Vol. 25; no. 4; pp. 1068 - 1079
• Main Authors: Camacho, Raul C., Polidori, David, Chen, Tao, Chen, Bin, Hsu, Helen Han, Gao, Bin, Marella, Mathieu, Lubomirski, Mariusz, Beavers, Traymon, Cabrera, Javier, Wong, Peggy, Nawrocki, Andrea R.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.04.2023; Wiley Subscription Services, Inc
• Subjects: Animals; Biopsy; Body weight; Body weight loss; caloricrestriction; Cholesterol; cynomolgus monkey; Diet; Diet, High-Fat; Dietary restrictions; Disease Models, Animal; Fatty liver; Fibrosis; High cholesterol diet; High fat diet; Insulin; Liver - pathology; Liver Cirrhosis - pathology; Liver diseases; Macaca fascicularis; NASH; Non-alcoholic Fatty Liver Disease - drug therapy; nonhuman primate; Obesity; Pioglitazone; Pioglitazone - therapeutic use; Weight control; pioglitazone; fibrosis; nonhuman primate; cynomolgus monkey; NASH; caloricrestriction
• ISSN: 1462-8902; 1463-1326
• DOI: 10.1111/dom.14955

Aim 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. Methods 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. Results 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). Conclusions 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.