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

Abstract

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.

Exploring the dynamic three-dimensional chromatin architecture and transcriptional landscape in goose liver tissues underlying metabolic adaptations induced by a high-fat diet

“…Animal models of NAFLD are predominantly established using high-fat dietary feeding, pharmacological intervention, and genetic modification. These models encompass a diverse range of mammals, spanning monkeys [ 47 ], mice [ 48 ], rats [ 49 ], pigs [ 50 ], rabbits [ 51 ], and geese [ 46 ], with each model offering distinct advantages and holding specific applicability. The goose HFD liver is significantly yellow compared to the dark red liver of the normal-diet group, and lipid droplet deposition has previously been reported in goose livers [ 52 , 53 ].…”

Nuciferine blocks MIB2-mediated CARD6 polyubiquitination and degradation in the amelioration of high fructose-induced liver lipid accumulation

“…More importantly, we studied and provided data for the inhibitory effect by nuciferine on MIB2 expression and subsequent K48-linked CARD6 polyubiquitination and degradation, suggesting MIB2 as the potential target of nuciferine. Pioglitazone, an agonist of PPARγ increasing insulin sensitivity, has shown its safety and effectiveness against nonalcoholic steatohepatitis in clinical trials 45 and animal models. 46 Here, our data indicated a novel mechanism by which pioglitazone reduced MIB2 expression to stabilize CARD6, finally alleviating high fructose-induced hepatocyte lipid accumulation.…”

Comparing different strategies to reduce hepatocellular damage in obese common marmosets (Callithrix jacchus)

“…In humans, macaques, dogs, and cats, reduced caloric intake with subsequent body weight loss reduces the risk for numerous sequelae of obesity. [16][17][18][19] However, no studies have specifically investigated whether there is reversal of hepatic damage when obesity is corrected in common marmosets. In other species with hepatocellular damage, it is common to start pharmaceutical treatment, regardless of underlying etiology.…”

“…In humans, macaques, dogs, and cats, reduced caloric intake with subsequent body weight loss reduces the risk for numerous sequelae of obesity 16–19 . However, no studies have specifically investigated whether there is reversal of hepatic damage when obesity is corrected in common marmosets.…”