Metabolic and hepatic effects of liraglutide, obeticholic acid and elafibranor in diet-induced obese mouse models of biopsy-confirmed nonalcoholic steatohepatitis
| العنوان: | Metabolic and hepatic effects of liraglutide, obeticholic acid and elafibranor in diet-induced obese mouse models of biopsy-confirmed nonalcoholic steatohepatitis |
|---|---|
| المؤلفون: | Kirstine S Tølbøl, Matthew P. Gillum, Niels Vrang, Kristoffer Tg Rigbolt, Michael Feigh, Maria Kristiansen, Jacob Jelsing, Sanne Skovgård Veidal, Henrik H. Hansen |
| المصدر: | World Journal of Gastroenterology |
| بيانات النشر: | Baishideng Publishing Group Inc, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Liver Cirrhosis, Male, Time Factors, Biopsy, Galectin 3, Peroxisome proliferator-activated receptor, Mice, Obese, Weight Gain, chemistry.chemical_compound, Chalcones, Non-alcoholic Fatty Liver Disease, Pathology, chemistry.chemical_classification, medicine.diagnostic_test, Gastroenterology, Elafibranor, Obeticholic acid, General Medicine, Basic Study, Liver biopsy, Liver, Glucagon-like peptide-1 receptor, medicine.drug, medicine.medical_specialty, Disease models, Chenodeoxycholic Acid, Diet, High-Fat, digestive system, Collagen Type I, 03 medical and health sciences, Farnesoid X receptor, Internal medicine, medicine, Animals, Obesity, Nonalcoholic steatohepatitis, Transcriptomics, business.industry, Liraglutide, nutritional and metabolic diseases, Lipid Metabolism, Fibrosis, digestive system diseases, Collagen Type I, alpha 1 Chain, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Endocrinology, chemistry, Pharmacodynamics, Propionates, business, Diet-induced obese |
| الوصف: | 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. |
| اللغة: | English |
| تدمد: | 2219-2840 1007-9327 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b7f6332ca98657d881a6a16dd63445ddTest http://europepmc.org/articles/PMC5768937Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....b7f6332ca98657d881a6a16dd63445dd |
| قاعدة البيانات: | OpenAIRE |
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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. 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