Published online Apr 28, 2018. doi: 10.3748/wjg.v24.i16.1748
Peer-review started: January 17, 2018
First decision: February 11, 2018
Revised: February 22, 2018
Accepted: February 26, 2018
Article in press: February 25, 2018
Published online: April 28, 2018
Non-alcoholic steatohepatitis (NASH) is an unmet medical need with no approved therapies. Studies here characterize the hepatic phenotype of two different diet-induced mouse models of NASH with a focus on mitochondrial function and ability to regulate oxidative damage.
Emerging evidence from cross-sectional human studies suggests a role for mitochondrial function in the development of NASH. As the pathogenesis of NASH remains largely unknown it is imperative to characterize potential therapeutic agents in a relevant preclinical model.
The primary objective was to characterize NASH histopathology (e.g., NASH activity score for steatosis, inflammation, ballooning and fibrosis) and function with a focus on mitochondrial biology and capacity to respond to oxidative stress. We contrast these endpoints in two distinct mouse strains (genetically obese Lepob/Lepob (ob/ob) and polygenic obesity-prone FATZO mice) on a previously validated NASH-inducing diet that is high in trans-fat, fructose and cholesterol (AMLN diet).
Development of NASH was assessed using blinded qualitative (HE stained sections) and quantitative (% collagen-stained area) methods. Mitochondria were assessed via transmission electron micrography and immunofluorescent detection of HSP60. Mitochondrial function was assessed in primary hepatocytes using Seahorse. Activity of superoxide dismutase and catalase were measured from whole liver tissue homogenates. Candidate genes from total liver RNA were measured using quantitative PCR.
Both ob/ob and FATZO mice developed NASH with concomitant obesity and hyperinsulinemia when challenged with AMLN diet for 12 wk, and was associated with mitochondrial accumulation and reduced function. The degree of hepatic fibrosis, however, was markedly greater in ob/ob mice and was associated with increased activity of superoxide dismutase (SOD), whereas FATZO mice displayed increased catalase activity. Antioxidant capacity, reflected as the ratio of catalase: SOD activity, was significantly perturbed in ob/ob mice with diet-induced NASH.
Both of these commonly available mouse models develop AMLN diet-induced NASH after 12 wk, associated with reduced mitochondrial function and perturbed morphology. The intrinsic capacity of the FATZO mice to increase antioxidant capacity in the face of impaired mitochondrial function/increased oxidative damage due to diet may be contributory towards the reduced level of fibrosis in that model.
The AMLN mouse model of NASH is gaining widespread academic and industry acceptance as a translatable model of NASH. These studies extend previous observations in the model to highlight mitochondrial dysfunction thus confirming the model as relevant for prosecution of therapeutic agents targeting improvement in mitochondrial function for NASH. Furthermore, the contrasting fibrosis between ob/ob and FATZO mice implicates the capacity to adapt to oxidative damage as a key regulator of liver fibrosis in diet-induced NASH.