Published online Sep 7, 2019. doi: 10.3748/wjg.v25.i33.4904
Peer-review started: April 26, 2019
First decision: May 24, 2019
Revised: June 28, 2019
Accepted: July 19, 2019
Article in press: July 19, 2019
Published online: September 7, 2019
Processing time: 134 Days and 21 Hours
Non-alcoholic steatohepatitis (NASH) is an obesity-associated liver disease with marked unmet medical need. Various diet-induced obese animal models of NASH have been employed in preclinical research, target discovery and drug development. The trans-fat containing amylin liver NASH (AMLN) diet, high in fat, fructose and cholesterol, has been widely used in ob/ob and C57BL/6J mice for reliably inducing metabolic and liver histopathological changes recapitulating hallmarks of NASH.
A recent ban on trans-fats as food additive has prompted the development of a trans-fat free high-fat diet capable of promoting a compatible level of disease in ob/ob and C57BL/6J mice.
The present study aimed to develop and characterize a liver biopsy-confirmed obese mouse model of NASH based on an isocaloric palmitic acid-enriched diet with a nutrient composition similar to the AMLN diet.
Male ob/ob mice were fed AMLN diet or a modified AMLN diet with trans-fat (Primex shortening) substituted by equivalent amounts of palm oil [Gubra Amylin NASH, (GAN) diet] for 8, 12 and 16 wk. In addition, C57BL/6J mice were fed AMLN or GAN diet for 28 wk. AMLN and GAN diets were isocaloric (40% fat kcal; 10% sucrose, 22% fructose, 2% cholesterol). Disease phenotyping included metabolic, liver biochemical/histopathological/transcriptomics as well as gut microbiome analyses.
In ob/ob mice, the GAN diet was more obesogenic and adipogenic compared to the AMLN diet. Whereas the GAN diet promoted impaired oral glucose tolerance in ob/ob mice, the AMLN diet had no effect on glucose regulation. The GAN and AMLN diets induced similar severity of liver biopsy-confirmed steatosis, lobular inflammation, hepatocyte ballooning and fibrotic lesions. In addition, hepatic transcriptome and gut microbiome changes were similar in ob/ob mice fed the GAN and AMLN diet. Also, C57BL/6J mice fed the GAN and AMLN developed a similar histological phenotype of mild to moderate fibrotic NASH.
Substitution of trans-fat (Primex in the AMLN diet) with saturated fat (palm oil in the GAN diet) promotes a consistent phenotype of biopsy-confirmed fibrotic NASH in both ob/ob and C57BL/6J mice.
GAN diet-based ob/ob and C57BL/6J mouse models of biopsy-confirmed NASH are applicable for preclinical characterization of novel NASH treatments.