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A Translational Mouse Model for NASH with Advanced Fibrosis and Atherosclerosis Expressing Key Pathways of Human Pathology

A Translational Mouse Model for NASH with Advanced Fibrosis and Atherosclerosis Expressing Key Pathways of Human Pathology

Authors :
Sridhar Radhakrishnan
Anita M. van den Hoek
Anita van Nieuwkoop
Martien P. M. Caspers
Robert Kleemann
Aswin L. Menke
Christa de Ruiter
Kanita Salic
Lars Verschuren
Nicole Worms
Joline Attema
Source :
Cells, 9, 9, 2014, Cells, Volume 9, Issue 9, Cells, Vol 9, Iss 2014, p 2014 (2020)
Publication Year :
2020

Abstract

Non-alcoholic steatohepatitis (NASH) is a fast-growing liver disorder that is associated with an increased incidence of cardiovascular disease and type 2 diabetes. Animal models adequately mimicking this condition are scarce. We herein investigate whether Ldlr&minus<br />/&minus<br />Leiden mice on different high-fat diets represent a suitable NASH model. Ldlr&minus<br />Leiden mice were fed a healthy chow diet or fed a high-fat diet (HFD) containing lard or a fast food diet (FFD) containing milk fat. Additionally, the response to treatment with obeticholic acid (OCA) was evaluated. Both high-fat diets induced obesity, hyperlipidemia, hyperinsulinemia, and increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Mice on both diets developed progressive macro- and microvesicular steatosis, hepatic inflammation, and fibrosis, along with atherosclerosis. HFD induced more severe hyperinsulinemia, while FFD induced more severe hepatic inflammation with advanced (F3) bridging fibrosis, as well as more severe atherosclerosis. OCA treatment significantly reduced hepatic inflammation and fibrosis, and it did not affect atherosclerosis. Hepatic transcriptome analysis was compared with human NASH and illustrated similarity. The present study defines a translational model of NASH with progressive liver fibrosis and simultaneous atherosclerosis development. By adaptation of the fat content of the diet, either insulin resistance (HFD) or hepatic inflammation and fibrosis (FFD) can be aggravated.

Details

Language :
English
Database :
OpenAIRE
Journal :
Cells, 9, 9, 2014, Cells, Volume 9, Issue 9, Cells, Vol 9, Iss 2014, p 2014 (2020)
Accession number :
edsair.doi.dedup.....a951c12414c252499d59ab033ca0be2b