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Open AccessArticle

New Rat Model of Advanced NASH Mimicking Pathophysiological Features and Transcriptomic Signature of The Human Disease

1
Liver Vascular Biology Research Group, Barcelona Hepatic Hemodynamic Laboratory, IDIBAPS Biomedical Research Institute, CIBEREHD, 08036 Barcelona, Spain
2
Barcelona Liver Bioservices, 08036 Barcelona, Spain
3
Bioinformatics Platform, CIBEREHD, 08036 Barcelona, Spain
4
Protective Strategies Against Hepatic Ischemia Reperfusion Injury Research Group, IDIBAPS & CIBEREHD, 08036, Barcelona, Spain
5
Hepatology, Department of Biomedical Research, University of Bern, 3012 Bern, Switzerland
*
Author to whom correspondence should be addressed.
Cells 2019, 8(9), 1062; https://doi.org/10.3390/cells8091062
Received: 22 July 2019 / Revised: 6 September 2019 / Accepted: 6 September 2019 / Published: 10 September 2019
Non-alcoholic steatohepatitis (NASH) is a major cause of chronic liver disease. However, most available animal models fail to reflect the whole spectrum of the disease. Liver fibrosis and portal hypertension are the strongest prognostic markers in advanced NASH. We herein aimed at developing a new model of NASH in male rats, obtained using a multi-hit protocol that combines the administration of a high fat and high-cholesterol diet with CCl4 and phenobarbital. Following this protocol, rats showed the full characteristics of advanced human NASH after 10 weeks and NASH with cirrhosis by 24 weeks. Specifically, our NASH rats exhibited: steatosis and metabolic syndrome, lipotoxicity, hepatocellular ballooning necrosis, inflammation and importantly, marked hepatic fibrosis and significant portal hypertension. Furthermore, a whole transcriptomic analysis of liver tissue from our rat model using next generation sequencing was compared with human NASH and illustrated the similarity of this pre-clinical model with the human disease. Pathway enrichment analysis showed that NASH animals shared a relevant number of central pathways involved in NASH pathophysiology, such as those related with cell death, as well as inflammatory or matrix remodeling. The present study defines a pre-clinical model of moderate and advanced NASH that mimics the human disease, including pathophysiologic characteristics and transcriptomic signature. View Full-Text
Keywords: steatosis; cirrhosis; hepatic fibrosis; portal hypertension; steatohepatitis steatosis; cirrhosis; hepatic fibrosis; portal hypertension; steatohepatitis
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Maeso-Díaz, R.; Boyer-Diaz, Z.; Lozano, J.J.; Ortega-Ribera, M.; Peralta, C.; Bosch, J.; Gracia-Sancho, J. New Rat Model of Advanced NASH Mimicking Pathophysiological Features and Transcriptomic Signature of The Human Disease. Cells 2019, 8, 1062.

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