Published online Jan 14, 2018. doi: 10.3748/wjg.v24.i2.179
Peer-review started: September 25, 2017
First decision: November 3, 2017
Revised: November 24, 2017
Accepted: December 5, 2017
Article in press: December 5, 2017
Published online: January 14, 2018
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 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.
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.
Core tip: The pharmacodynamics of three compounds in advanced clinical development for the treatment of nonalcoholic steatohepatitis (NASH), including liraglutide, elafibranor and obeticholic acid, were evaluated in wild-type and genetically (ob/ob) obese mouse models of NASH. Prior to treatment, all mice underwent liver biopsy for confirmation and stratification of liver steatosis and fibrosis. Within-subject comparisons were performed on changes in liver histopathology. Wild-type and ob/ob-NASH obese mice showed distinct treatment effects of liraglutide, OCA, and elafibranor, being in general agreement with corresponding findings in clinical trials for NASH. In conclusion, the two obese mouse models of NASH show clinical translatability with respect to disease etiology, histopathology and drug treatment effects, which supports their utility in preclinical drug development.