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 N.B.
AU - Hansen, Henrik H.
AU - Veidal, Sanne S.
AU - Rigbolt, Kristoffer T.G.
AU - Gillum, Matthew P.
AU - Jelsing, Jacob
AU - Vrang, Niels
AU - Feigh, Michael
N1 - PJ
PY - 2018
Y1 - 2018
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 andob/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 andob/ob-NASH mouse models of NASH for probing the therapeutic efficacy of compounds in preclinical drug development for NASH.
AB - 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 andob/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 andob/ob-NASH mouse models of NASH for probing the therapeutic efficacy of compounds in preclinical drug development for NASH.
KW - Journal Article
KW - Farnesoid X receptor
KW - Liver biopsy
KW - Pathology
KW - Glucagon-like peptide- 1 receptor
KW - Pharmacodynamics
KW - Nonalcoholic steatohepatitis
KW - Disease models
KW - Peroxisome proliferator-activated receptor
KW - Transcriptomics
KW - Fibrosis
KW - Glucagon-like peptide-1 receptor
U2 - 10.3748/wjg.v24.i2.179
DO - 10.3748/wjg.v24.i2.179
M3 - Journal article
C2 - 29375204
SN - 1007-9327
VL - 24
SP - 179
EP - 194
JO - World Journal of Gastroenterology
JF - World Journal of Gastroenterology
IS - 2
ER -