Basic Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jan 14, 2018; 24(2): 179-194
Published online Jan 14, 2018. doi: 10.3748/wjg.v24.i2.179
Metabolic and hepatic effects of liraglutide, obeticholic acid and elafibranor in diet-induced obese mouse models of biopsy-confirmed nonalcoholic steatohepatitis
Kirstine S Tølbøl, Maria NB Kristiansen, Henrik H Hansen, Sanne S Veidal, Kristoffer TG Rigbolt, Matthew P Gillum, Jacob Jelsing, Niels Vrang, Michael Feigh
Kirstine S Tølbøl, Maria NB Kristiansen, Henrik H Hansen, Sanne S Veidal, Kristoffer TG Rigbolt, Jacob Jelsing, Niels Vrang, Michael Feigh, Gubra Aps, Hørsholm DK-2970, Denmark
Kirstine S Tølbøl, Maria NB Kristiansen, Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark
Kirstine S Tølbøl, Matthew P Gillum, Section for Metabolic Imaging and Liver Metabolism, The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark
Niels Vrang, Department of Chemistry, Faculty of Science, University of Copenhagen, Copenhagen DK-2200, Denmark
Author contributions: Tølbøl KS and Kristiansen MNB contributed equally to the work; Jelsing J, Vrang N and Feigh M designed the study; Tølbøl KS, Kristiansen MNB, Veidal SS and Rigbolt KTG acquired and analysed data; Tølbøl KS, Kristiansen MNB, Hansen HH, Veidal SS, Rigbolt KTG, Gillum MP, Jelsing J, Vrang N and Feigh M interpreted the data and contributed to writing the article, editing and reviewing, all authors approved the final version of the article.
Supported by Innovation Fund Denmark, KST; No. 5016-00168B; and MNBK, No. 5189-00040B.
Institutional animal care and use committee statement: All animal experiments conformed to the internationally accepted principles for the care and use of laboratory animals (Licence No. 2013-15-2934-00784, The Animal Experiments Inspectorate, Denmark).
Conflict-of-interest statement: The authors declare no conflict of interest.
Data sharing statement: No additional data are available.
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: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Kirstine S Tølbøl, MSc, Research Scientist, Gubra Aps, Hørsholm Kongevej 11B, Hørsholm DK-2970, Denmark. kst@gubra.dk
Telephone: +45-23-1522650
Received: September 25, 2017
Peer-review started: September 25, 2017
First decision: November 3, 2017
Revised: November 24, 2017
Accepted: December 5, 2017
Article in press: December 5, 2017
Published online: January 14, 2018
Processing time: 110 Days and 20.4 Hours
ARTICLE HIGHLIGHTS
Research background

Although various diet-induced obese mouse models of nonalcoholic steatohepatitis (NASH) are highly applicable in preclinical drug development, none of these models have so far been systematically evaluated with respect to comparing individual pharmacodynamics of several important compound classes in current clinical development for NASH.

Research motivation

Comparison of preclinical treatment effects of potential anti-NASH compounds is currently hampered by the absence of head-to-head pharmacological studies in experimental models of NASH. Moreover, baseline NASH disease heterogeneity is often overlooked in pharmacological studies which may introduce unintentional variability in treatment responses, thereby narrowing the window for detection of therapeutic effects of potential anti-NASH compounds.

Research objectives

The present study aimed to characterize within-subject treatment responses to liraglutide, obeticholic acid and elafibranor in two obese mouse models of biopsy-confirmed NASH.

Research methods

Comparative treatment studies were conducted in male wild-type mice (DIO-NASH) and Lepob/ob (ob/ob-NASH) mice fed a diet high in trans-fat, fructose and cholesterol. Liver biopsy was applied for stratification of liver steatosis and fibrosis, using the nonalcoholic fatty liver disease activity score (NAS) and fibrosis staging system. Individual biopsy-confirmed histopathology also allowed for evaluation of within-subject treatment responses based on differences in baseline vs. endpoint histomorphometry. DIO-NASH and ob/ob-NASH mice were treated with vehicle, liraglutide, obeticholic acid, or elafibranor for 8 weeks. Metabolic, histomorphological and quantitative histological effects of each compound were compared in the two models of biopsy-confirmed NASH.

Research results

Only liraglutide and elafibranor reduced body weight in DIO-NASH and ob/ob-NASH mice. Liraglutide improved steatosis scores in DIO-NASH mice only. Whereas elafibranor and OCA both reduced hepatic steatosis and inflammation scores in both models, only elafibranor also improved fibrosis stage. Owing to a marked reduction in liver weight, liraglutide and OCA lowered total liver fat, collagen 1a1 and galectin-3 content. Individual drug effects on NASH histological endpoints were supported by global gene expression (RNA sequencing) and liver lipid biochemistry.

Research conclusions

DIO-NASH and ob/ob-NASH mice show good clinical translatability with respect to disease etiology, histopathology and therapeutic effects of compounds in late-stage clinical development for NASH.

Research perspectives

The present data supports the utility of DIO-NASH and ob/ob-NASH mice for preclinical evaluation of the treatment efficacy of potential novel anti-NASH compounds. As also applied in clinical trials for NASH, biopsy-confirmed histopathology in the two obese mouse models of NASH allows for stratification of disease severity prior to treatment start and improves detection of treatment efficacy of test compounds by considering within-subject responses.