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Fatty Liver Disease and Multi-System Complications | EK28


The guinea pig NASH transcriptome resembles that of human patients


Mar 22, 2021 12:00am ‐ Mar 22, 2021 12:00am

Description

The guinea pig NASH transcriptome resembles that of human patients Skat-Rørdam Josephine1, Ipsen David Højland3, Seemann Stefan Ernst2, Latta Markus3, Lykkesfeldt Jens1, Tveden-Nyborg Pernille1 1Department of Veterinary and Animal Sciences, Section of Experimental Animal Models, Faculty of Health and Medical Sciences, University of Copenhagen. 2 Department of Veterinary and Animal Sciences, Section for Animal Genetics, Bioinformatics and Breeding, Center for non-coding RNA in Technology and Health, University of Copenhagen. 3Liver Disease Research, Global Drug Discovery, Novo Nordisk A/S. Currently, the field of non-alcoholic steatohepatitis (NASH) is challenged by the limited availability of predictive preclinical models that recapitulate the disease spectrum. This compromises validity of findings and reduces the success-rate of preclinical studies, ultimately delaying the development of novel treatment modalities for millions of patients worldwide. The guinea pig model develops NASH with histopathological hallmarks similar to humans and bridging fibrosis (F3) within 25 weeks on a high fat/cholesterol diet. To further elucidate the translational potential of this model, this study compared the transcriptome in guinea pigs with NASH-associated fibrosis to two human datasets; GSE126848 & GSE49541, derived from patients with mild or advanced NASH respectively. In addition, the guinea pig NASH transcriptome was compared to transcriptomes from three murine NAFLD/NASH models; GSE52748, GSE62805, GSE67680. RNA-sequencing was performed on 6 NASH and 6 control guinea pigs and identified 6,683 differentially expressed genes, revealing a highly differentiated transcriptome in NASH compared to healthy controls. Of the top 100 genes associated with human NASH (as determined by the DISEASES database), 60% were re-covered as differentially expressed genes in guinea pigs. Gene set enrichment analysis revealed higher similarity between guinea pig and human (GSE49541) datasets, compared to the included murine models. Correlation to the degree of fibrosis revealed nine genes with a correlation coefficient above 0.8, supporting a potential link to NASH-induced hepatic fibrosis. All nine genes showed similar expression patterns in patients with advanced fibrotic NASH, hence may represent potential biomarkers of the disease and/or targets for future treatment strategies. In conclusion, the guinea pig transcriptome in advanced NASH with hepatic fibrosis has a high similarity to human patients with advanced NASH. This substantiates the translational value of this preclinical model, also compared to transcriptomes from other available murine models. The identification of nine genes highly correlated to the degree of fibrosis, supports the value of the guinea pig model in the quest of finding reliable biomarkers and treatments for this disease.

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