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
Although various diet-induced obese mouse models of nonalcoholic steatohepatitis (NASH) are highly applicable in preclinical drug development, none of these models have so far been systematically evaluated with respect to comparing individual pharmacodynamics of several important compound classes in current clinical development for NASH.
Comparison of preclinical treatment effects of potential anti-NASH compounds is currently hampered by the absence of head-to-head pharmacological studies in experimental models of NASH. Moreover, baseline NASH disease heterogeneity is often overlooked in pharmacological studies which may introduce unintentional variability in treatment responses, thereby narrowing the window for detection of therapeutic effects of potential anti-NASH compounds.
The present study aimed to characterize within-subject treatment responses to liraglutide, obeticholic acid and elafibranor in two obese mouse models of biopsy-confirmed NASH.
Comparative treatment studies were conducted in male wild-type mice (DIO-NASH) and Lepob/ob (ob/ob-NASH) mice fed a diet high in trans-fat, fructose and cholesterol. Liver biopsy was applied for stratification of liver steatosis and fibrosis, using the nonalcoholic fatty liver disease activity score (NAS) and fibrosis staging system. Individual biopsy-confirmed histopathology also allowed for evaluation of within-subject treatment responses based on differences in baseline vs. endpoint histomorphometry. DIO-NASH and ob/ob-NASH mice were treated with vehicle, liraglutide, obeticholic acid, or elafibranor for 8 weeks. Metabolic, histomorphological and quantitative histological effects of each compound were compared in the two models of biopsy-confirmed NASH.
Only liraglutide and elafibranor reduced body weight in DIO-NASH and ob/ob-NASH mice. Liraglutide improved steatosis scores in DIO-NASH mice only. Whereas elafibranor and OCA both reduced hepatic steatosis and inflammation scores in both models, only elafibranor also improved fibrosis stage. Owing to a marked reduction in liver weight, liraglutide and OCA lowered total liver fat, collagen 1a1 and galectin-3 content. 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 mice show good clinical translatability with respect to disease etiology, histopathology and therapeutic effects of compounds in late-stage clinical development for NASH.
The present data supports the utility of DIO-NASH and ob/ob-NASH mice for preclinical evaluation of the treatment efficacy of potential novel anti-NASH compounds. As also applied in clinical trials for NASH, biopsy-confirmed histopathology in the two obese mouse models of NASH allows for stratification of disease severity prior to treatment start and improves detection of treatment efficacy of test compounds by considering within-subject responses.