Human translatability of the GAN diet-induced obese mouse model of non-alcoholic steatohepatitis

Abstract

Background: Animal models of non-alcoholic steatohepatitis (NASH) are important tools in preclinical research and drug discovery. Gubra-Amylin NASH (GAN) diet-induced obese (DIO) mice represent a model of fibrosing NASH. The present study directly assessed the clinical translatability of the model by head-to-head comparison of liver biopsy histological and transcriptome changes in GAN DIO-NASH mouse and human NASH patients. Methods: C57Bl/6 J mice were fed chow or the GAN diet rich in saturated fat (40%), fructose (22%) and cholesterol (2%) for ≥38 weeks. Metabolic parameters as well as plasma and liver biomarkers were assessed. Liver biopsy histology and transcriptome signatures were compared to samples from human lean individuals and patients diagnosed with NASH. Results: Liver lesions in GAN DIO-NASH mice showed similar morphological characteristics compared to the NASH patient validation set, including macrosteatosis, lobular inflammation, hepatocyte ballooning degeneration and periportal/perisinusoidal fibrosis. Histomorphometric analysis indicated comparable increases in markers of hepatic lipid accumulation, inflammation and collagen deposition in GAN DIO-NASH mice and NASH patient samples. Liver biopsies from GAN DIO-NASH mice and NASH patients showed comparable dynamics in several gene expression pathways involved in NASH pathogenesis. Consistent with the clinical features of NASH, GAN DIO-NASH mice demonstrated key components of the metabolic syndrome, including obesity and impaired glucose tolerance. Conclusions: The GAN DIO-NASH mouse model demonstrates good clinical translatability with respect to the histopathological, transcriptional and metabolic aspects of the human disease, highlighting the suitability of the GAN DIO-NASH mouse model for identifying therapeutic targets and characterizing novel drug therapies for NASH.

Investigating Transcriptional Dynamics Changes and Time-Dependent Marker Gene Expression in the Early Period After Skeletal Muscle Injury in Rats

“…From the perspective of homologous gene expression and conservation through evolution, the study of diseases or physiological processes based on time-series changes in model organisms lays a foundation for cross-species inference or translational research among related species (Parikh et al, 2010;Hardison, 2016;Zhu et al, 2018). Based on detailed studies of gene expression and transcription kinetics in biological processes, research at the level of gene-expression changes after injury has significant reference value for research on translational medicine and for the further exploration of crossspecies translation based on the same or similar biological processes among related species (Czarnewski et al, 2019;Hansen et al, 2020).…”

Nuclear hormone and peptide hormone therapeutics for NAFLD and NASH

“…Furthermore, studying new therapies in rare cholestatic liver diseases such as primary biliary cholangitis and primary sclerosing cholangitis will allow earlier proof of concept assessment in humans. Continued upstream work to advance translatable in vitro cell models, such as hepatic cell organoids [ 3 ], and in vivo preclinical models, such as Gubra-Amylin NASH DIO mice [ 4 ], will aid more in-depth disease understanding and support screening of novel pharmacotherapies. Together, these systematic efforts will catalyze the discovery of new therapeutic strategies with increased innovation so that transformative medicines can be effectively and efficiently developed.…”

“…These challenges are diverse, numerous, and can impact the entire therapeutic discovery process and evaluation. At the most basic level, optimized in vitro [ 3 ] and in vivo [ 4 ] models that recapitulate the human condition are progressing, but their utility to identify novel targets and predict translational efficacy are still lacking. This is at least in part due to the heterogeneity of the clinical disease presentation and lack of concrete clinical comparisons.…”

Considerations When Choosing High-Fat, High-Fructose, and High-Cholesterol Diets to Induce Experimental Nonalcoholic Fatty Liver Disease in Laboratory Animal Models

“…Replacing Primex® with palm oil ( Table 1 ) in the AMLN diet drives a remarkably similar phenotype in C57BL/6J mice ( 17 , 36 ). Palm oil, which is part of Primex® and Primex-Z®, contains mainly palmitic acid (∼42% of total fat) (for complete fatty acid profiles of the AMLN diet and modified fat versions, see Supplemental Table 1 ).…”