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
Abstract
AIM

To evaluate the pharmacodynamics of compounds in clinical development for nonalcoholic steatohepatitis (NASH) in obese mouse models of biopsy-confirmed NASH.

METHODS

Male wild-type C57BL/6J mice (DIO-NASH) and Lepob/ob (ob/ob-NASH) mice were fed a diet high in trans-fat (40%), fructose (20%) and cholesterol (2%) for 30 and 21 wk, respectively. Prior to treatment, all mice underwent liver biopsy for confirmation and stratification of liver steatosis and fibrosis, using the nonalcoholic fatty liver disease activity score (NAS) and fibrosis staging system. The mice were kept on the diet and received vehicle, liraglutide (0.2 mg/kg, SC, BID), obeticholic acid (OCA, 30 mg/kg PO, QD), or elafibranor (30 mg/kg PO, QD) for eight weeks. Within-subject comparisons were performed on changes in steatosis, inflammation, ballooning degeneration, and fibrosis scores. In addition, compound effects were evaluated by quantitative liver histology, including percent fractional area of liver fat, galectin-3, and collagen 1a1.

RESULTS

Liraglutide and elafibranor, but not OCA, reduced body weight in both models. Liraglutide improved steatosis scores in DIO-NASH mice only. Elafibranor and OCA reduced histopathological scores of hepatic steatosis and inflammation in both models, but only elafibranor reduced fibrosis severity. Liraglutide and OCA reduced total liver fat, collagen 1a1, and galectin-3 content, driven by significant reductions in liver weight. The individual drug effects on NASH histological endpoints were supported by global gene expression (RNA sequencing) and liver lipid biochemistry.

CONCLUSION

DIO-NASH and ob/ob-NASH mouse models show distinct treatment effects of liraglutide, OCA, and elafibranor, being in general agreement with corresponding findings in clinical trials for NASH. The present data therefore further supports the clinical translatability and utility of DIO-NASH and ob/ob-NASH mouse models of NASH for probing the therapeutic efficacy of compounds in preclinical drug development for NASH.

Keywords: Nonalcoholic steatohepatitis, Disease models, Pathology, Fibrosis, Liver biopsy, Transcriptomics, Pharmacodynamics, Glucagon-like peptide-1 receptor, Peroxisome proliferator-activated receptor, Farnesoid X receptor

Core tip: The pharmacodynamics of three compounds in advanced clinical development for the treatment of nonalcoholic steatohepatitis (NASH), including liraglutide, elafibranor and obeticholic acid, were evaluated in wild-type and genetically (ob/ob) obese mouse models of NASH. Prior to treatment, all mice underwent liver biopsy for confirmation and stratification of liver steatosis and fibrosis. Within-subject comparisons were performed on changes in liver histopathology. Wild-type and ob/ob-NASH obese mice showed distinct treatment effects of liraglutide, OCA, and elafibranor, being in general agreement with corresponding findings in clinical trials for NASH. In conclusion, the two obese mouse models of NASH show clinical translatability with respect to disease etiology, histopathology and drug treatment effects, which supports their utility in preclinical drug development.