Metabolic and hepatic effects of liraglutide, obeticholic acid and elafibranor in diet-induced obese mouse models of biopsy-confirmed nonalcoholic steatohepatitis
Liver Cirrhosis
Male
0301 basic medicine
Time Factors
Biopsy
Galectin 3
Mice, Obese
Disease models
Chenodeoxycholic Acid
Diet, High-Fat
Collagen Type I
03 medical and health sciences
Chalcones
Farnesoid X receptor
Non-alcoholic Fatty Liver Disease
Journal Article
Pathology
Animals
Obesity
Nonalcoholic steatohepatitis
Transcriptomics
2. Zero hunger
Glucagon-like peptide- 1 receptor
Peroxisome proliferator-activated receptor
Liver biopsy
Basic Study
Liraglutide
Lipid Metabolism
Fibrosis
3. Good health
Collagen Type I, alpha 1 Chain
Mice, Inbred C57BL
Disease Models, Animal
Pharmacodynamics
Liver
Glucagon-like peptide-1 receptor
Propionates
DOI:
10.3748/wjg.v24.i2.179
Publication Date:
2018-01-14T05:53:18Z
AUTHORS (9)
ABSTRACT
To evaluate the pharmacodynamics of compounds in clinical development for nonalcoholic steatohepatitis (NASH) in obese mouse models of biopsy-confirmed NASH.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.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.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.
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