Nonalcoholic Fatty Liver Disease (NAFLD) in Obese Rhesus Monkeys Provides the First Animal Model that Accurately Reflects the Human Condition
Authors: Hansen Barbara Caleen , Liang Zhigang , Sun Fengjiao , Yang Zunyuan , Tang Chungui , Chen Zhengli , Yubo Shen , Yao Zunwei , Wu Mingling , Chen Yuanhai , Gao Fabao , Zeng Wen 
Published: November 2023

None of the many previous animal models of NAFLD/NASH, whether genetic mouse models or aberrant dietary challenges, replicate or fully reflect either the metabolic pathophysiology or the histopathology of patients with NAFLD/NASH. We report for the first time the development and characterization of NASH in middle‐aged naturally overweight nonhuman primates. This colony has been maintained continuously on a healthy low fat high fiber diet and by all parameters, it is clear that these rhesus monkeys have developed the same disease as develops so commonly in humans.

Methods

NAFLD/NASH histopathology was examined in 37 male rhesus monkeys (7–20yrs, 7–18kg; 25 of which were significantly overweight >12 kg). These nonhuman primates have exhibited in detail the characteristics of the metabolic syndrome as seen in humans, including normoglycemia, hyperinsulinemia, insulin resistance, hypertension, and dyslipidemia, together with additional circulating biomarkers.

Results

By ultrasound evaluation of the 37 monkeys, 6 were identified to be normal with no steatosis (<5%); 12 had mild steatosis (5–10%) and 19 had moderate steatosis (10–30%). Dual‐energy CT (DECT) was used to quantify liver fat content. DECT quantified 6, 12, and 19 monkeys into the normal group <5% fat, the mild group with 5–10% fat, and the moderate group with 10 to 30% fat. The mild and moderate groups had significantly higher body weights (p<0.001) and higher C‐peptide levels than the normal group (p<0.01). In 24 of these 37 monkeys, liver needle biopsies were performed and evaluated by standard stains. Separately and blindly, the NAFLD Activity Score (NAS; by H&E) and then the fibrosis score (by Masson) were determined for each biopsy specimen. All 6 of the monkeys that were normal by DECT had normal NAS scores. 50% of the monkeys that were in the mild group all had NAS scores of 4; among the 10 monkeys in the mod group that were biopsied, 9 of 10 had NASH (5 with NAS scores of 4, and 4 with NAS scores of 5–6) and 1 had simple steatosis (SS). Masson results showed that of the 4 with NAS scores of 5–6, 3 were in stages 2–3, and 1 was in stage 1a. Among the 5 with NAS score of 4, 4 were in 0–1c stage. The 4 in the mild group with NAS scores of 3–4 wee in 1c‐3 stages. SS cases were in the 1a–1c stage. In conclusion, DECT is important for noninvasive liver fat quantification in obese patients and the NAFLD monkey model shows the same specific liver pathology and circulating biomarkers as humans.

Conclusions

We conclude that this nonhuman primate model, permitting both repeated liver biopsies and imaging studies, provides new opportunities to understand the pathogenesis as well as to examine in detail (with sequential repeated liver biopsies and longitudinal metabolic biomarkers) both the progression of the disease and its response to new therapeutic agents.