Roth JD, Feigh M, Veidal SS, Fensholdt LK, Rigbolt KT, Hansen HH, Chen LC, Petitjean M, Friley W, Vrang N, Jelsing J, Young M. INT-767 improves histopathological features in a diet-induced ob/ob mouse model of biopsy-confirmed non-alcoholic steatohepatitis. World J Gastroenterol 2018; 24(2): 195-210 [PMID: 29375205 DOI: 10.3748/wjg.v24.i2.195]
Corresponding Author of This Article
Henrik H Hansen, PhD, Principal Scientist, Pharmacology, Gubra, Kongevej 11B, Hoersholm DK-2970, Denmark. hbh@gubra.dk
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Basic Study
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Roth JD, Feigh M, Veidal SS, Fensholdt LK, Rigbolt KT, Hansen HH, Chen LC, Petitjean M, Friley W, Vrang N, Jelsing J, Young M. INT-767 improves histopathological features in a diet-induced ob/ob mouse model of biopsy-confirmed non-alcoholic steatohepatitis. World J Gastroenterol 2018; 24(2): 195-210 [PMID: 29375205 DOI: 10.3748/wjg.v24.i2.195]
World J Gastroenterol. Jan 14, 2018; 24(2): 195-210 Published online Jan 14, 2018. doi: 10.3748/wjg.v24.i2.195
INT-767 improves histopathological features in a diet-induced ob/ob mouse model of biopsy-confirmed non-alcoholic steatohepatitis
Jonathan D Roth, Michael Feigh, Sanne S Veidal, Louise KD Fensholdt, Kristoffer T Rigbolt, Henrik H Hansen, Li C Chen, Mathieu Petitjean, Weslyn Friley, Niels Vrang, Jacob Jelsing, Mark Young
Jonathan D Roth, Mark Young, Intercept Pharmaceuticals, Intercept Pharmaceuticals, San Diego, CA 92121, United States
Michael Feigh, Sanne S Veidal, Louise KD Fensholdt, Kristoffer T Rigbolt, Henrik H Hansen, Niels Vrang, Jacob Jelsing, Gubra, Hoersholm DK-2970, Denmark
Li C Chen, Mathieu Petitjean, PharmaNest, Genesis Imaging Services, Princeton, NJ 08540, United States
Weslyn Friley, Qualyst Transporter Solutions, Durham, NC 27713, United States
Author contributions: Studies were designed by Roth JD, Feigh M, Petitjean M and Young M; Fensholdt LKD Fensholdt, Veidal SS, Rigbolt KT, Chen LC and Friley W performed the majority of experiments; Hansen HH and Roth JD wrote the paper with significant contributions to data analyses and editing by all co-authors.
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: Jonathan Roth and Mark Young are employed by and hold equity in Intercept Pharmaceuticals, Inc. All other authors have nothing to disclose.
Data sharing statement: No additional data are available.
Correspondence to: Henrik H Hansen, PhD, Principal Scientist, Pharmacology, Gubra, Kongevej 11B, Hoersholm DK-2970, Denmark. hbh@gubra.dk
Telephone: +45-23-1522651
Received: October 23, 2017 Peer-review started: October 25, 2017 First decision: November 14, 2017 Revised: November 24, 2017 Accepted: December 5, 2017 Article in press: December 5, 2017 Published online: January 14, 2018 Processing time: 82 Days and 23.7 Hours
Core Tip
Core tip: The studies contained herein evaluated the preclinical efficacy of INT-767, a dual FXR/TGR5 agonist, in a mouse model of diet-induced and biopsy-confirmed non-alcoholic steatohepatitis (NASH). Rigorous analyses for NASH histological endpoints and markers were conducted including blinded qualitative and quantitative scoring using standard microscopy as well as advanced morphometric fibrosis and steatosis features using second harmonic generation imaging and two-photon fluorescence excitation. INT-767 promoted dose-dependent improvements in fibrosis, steatosis, inflammation and ballooning degeneration. The effects of INT-767 and obeticholic acid (OCA) were also compared for histological efficacy, gene expression and tissue distribution. The preclinical data suggest that INT-767 is a more potent FXR receptor agonist, and is expected to have therapeutic effects at lower doses than OCA.
