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Metabolic and hepatic effects of liraglutide, obeticholic acid and elafibranor in diet-induced obese mouse models of biopsy-confirmed nonalcoholic steatohepatitis.
World J Gastroenterol. 2018 Jan 14; 24(2):179-194.WJ

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 Lep ob/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.

Authors+Show Affiliations

Gubra Aps, Hørsholm DK-2970, Denmark.Gubra Aps, Hørsholm DK-2970, Denmark. kst@gubra.dk.Gubra Aps, Hørsholm DK-2970, Denmark.Gubra Aps, Hørsholm DK-2970, Denmark.Gubra Aps, Hørsholm DK-2970, Denmark.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.Gubra Aps, Hørsholm DK-2970, Denmark.Gubra Aps, Hørsholm DK-2970, Denmark.Gubra Aps, Hørsholm DK-2970, Denmark.

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

29375204

Citation

Tølbøl, Kirstine S., et al. "Metabolic and Hepatic Effects of Liraglutide, Obeticholic Acid and Elafibranor in Diet-induced Obese Mouse Models of Biopsy-confirmed Nonalcoholic Steatohepatitis." World Journal of Gastroenterology, vol. 24, no. 2, 2018, pp. 179-194.
Tølbøl KS, Kristiansen MN, Hansen HH, et al. Metabolic and hepatic effects of liraglutide, obeticholic acid and elafibranor in diet-induced obese mouse models of biopsy-confirmed nonalcoholic steatohepatitis. World J Gastroenterol. 2018;24(2):179-194.
Tølbøl, K. S., Kristiansen, M. N., Hansen, H. H., Veidal, S. S., Rigbolt, K. T., Gillum, M. P., Jelsing, J., Vrang, N., & Feigh, M. (2018). Metabolic and hepatic effects of liraglutide, obeticholic acid and elafibranor in diet-induced obese mouse models of biopsy-confirmed nonalcoholic steatohepatitis. World Journal of Gastroenterology, 24(2), 179-194. https://doi.org/10.3748/wjg.v24.i2.179
Tølbøl KS, et al. Metabolic and Hepatic Effects of Liraglutide, Obeticholic Acid and Elafibranor in Diet-induced Obese Mouse Models of Biopsy-confirmed Nonalcoholic Steatohepatitis. World J Gastroenterol. 2018 Jan 14;24(2):179-194. PubMed PMID: 29375204.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Metabolic and hepatic effects of liraglutide, obeticholic acid and elafibranor in diet-induced obese mouse models of biopsy-confirmed nonalcoholic steatohepatitis. AU - Tølbøl,Kirstine S, AU - Kristiansen,Maria Nb, AU - Hansen,Henrik H, AU - Veidal,Sanne S, AU - Rigbolt,Kristoffer Tg, AU - Gillum,Matthew P, AU - Jelsing,Jacob, AU - Vrang,Niels, AU - Feigh,Michael, PY - 2017/09/25/received PY - 2017/11/24/revised PY - 2017/12/05/accepted PY - 2018/1/30/entrez PY - 2018/1/30/pubmed PY - 2018/8/28/medline KW - Disease models KW - Farnesoid X receptor KW - Fibrosis KW - Glucagon-like peptide-1 receptor KW - Liver biopsy KW - Nonalcoholic steatohepatitis KW - Pathology KW - Peroxisome proliferator-activated receptor KW - Pharmacodynamics KW - Transcriptomics SP - 179 EP - 194 JF - World journal of gastroenterology JO - World J. Gastroenterol. VL - 24 IS - 2 N2 - 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 Lep ob/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. SN - 2219-2840 UR - https://www.unboundmedicine.com/medline/citation/29375204/Metabolic_and_hepatic_effects_of_liraglutide_obeticholic_acid_and_elafibranor_in_diet_induced_obese_mouse_models_of_biopsy_confirmed_nonalcoholic_steatohepatitis_ L2 - http://www.wjgnet.com/1007-9327/full/v24/i2/179.htm DB - PRIME DP - Unbound Medicine ER -