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

Maeso-Díaz Maeso-Díaz,Peralta Peralta,Gracia-Sancho Gracia-Sancho,Boyer-Diaz Boyer-Diaz,Bosch Bosch,Ortega-Ribera Ortega-Ribera,Lozano Lozano

doi:10.3390/cells8091062

Abstract

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.

Highlights

Non-alcoholic fatty liver disease (NAFLD) is considered a new epidemy in chronic liver diseases.its prevalence has been estimated to be as high as 25% in the general population and even higher (>70%) in patients with other metabolic risk factors like obesity and diabetes [1,2]
Total cholesterol and low density lipoprotein-cholesterol (LDL)-cholesterol were significantly elevated in plasma from non-alcoholic steatohepatitis (NASH)-CH animals (Figure 1C), while no statistical differences were observed in the NASH group
Both groups of NASH animals had fasting hyperinsulinemia accompanied by an abnormal glucose tolerance test response (Figure 1E,F), features associated with insulin resistance

Summary

Introduction

Non-alcoholic fatty liver disease (NAFLD) is considered a new epidemy in chronic liver diseases.its prevalence has been estimated to be as high as 25% in the general population and even higher (>70%) in patients with other metabolic risk factors like obesity and diabetes [1,2]. Non-alcoholic fatty liver disease (NAFLD) is considered a new epidemy in chronic liver diseases. It is well known than up to 30% of the NAFLD population will further progress and develop non-alcoholic steatohepatitis (NASH), the more severe form of fatty liver disease. NASH can progress to the end-stages of chronic liver disease, including cirrhosis and hepatocellular carcinoma (HCC) [3]. In view of the increasing incidence of NAFLD worldwide, a large number of translational laboratories are focused on understanding new aspects of NASH pathophysiology, on discovering specific and non-invasive diagnostic biomarkers, and developing effective pharmacologic treatments [4]. The lack of reliable NASH animal models remains a limitation for studying the disease and

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Conclusion