Basic Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Apr 28, 2018; 24(16): 1748-1765
Published online Apr 28, 2018. doi: 10.3748/wjg.v24.i16.1748
Nonalcoholic steatohepatitis severity is defined by a failure in compensatory antioxidant capacity in the setting of mitochondrial dysfunction
Michelle L Boland, Stephanie Oldham, Brandon B Boland, Sarah Will, Jean-Martin Lapointe, Silvia Guionaud, Christopher J Rhodes, James L Trevaskis
Michelle L Boland, Stephanie Oldham, Brandon B Boland, Sarah Will, Christopher J Rhodes, James L Trevaskis, Cardiovascular and Metabolic Diseases, MedImmune LLC, Gaithersburg, MD 20878, United States
Jean-Martin Lapointe, Pathology, MedImmune Ltd., Cambridge CB21 6GH, United Kingdom
Silvia Guionaud, Pathology, Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca, Cambridge CB22 3AT, United Kingdom
Author contributions: Boland ML and Trevaskis JL conceived of the project; Boland ML, Rhodes CJ and Trevaskis JL designed and interpreted experiments; Boland ML, Oldham S, Boland BB, Will S, Lapointe JM and Guionaud S acquired and analyzed data; Boland ML, Boland BB, Rhodes CJ and Trevaskis JL wrote and edited the manuscript.
Supported by MedImmune.
Institutional animal care and use committee statement: All animal experiments were conducted in accordance with policies of the NIH Guide for the Care and Use of Laboratory Animals and the Institutional Animal Care and Use Committee (IACUC) of MedImmune, LLC. Specific protocols used in this study were approved by the MedImmune IACUC, protocol number MI-16-0034.
Conflict-of-interest statement: All authors are current employees and/or stockholders of MedImmune/AstraZeneca.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: James L Trevaskis, PhD, Principal Scientist, Cardiovascular and Metabolic Diseases, MedImmune, LLC, Gaithersburg, MD 20878, United States.
Telephone: +1-301-3986695
Received: January 17, 2018
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
Research background

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.

Research motivation

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.

Research objectives

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).

Research methods

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.

Research results

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.

Research conclusions

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.

Research perspectives

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.