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J Hepatol. 2016 Sep;65(3):579-88. doi: 10.1016/j.jhep.2016.05.005. Epub 2016 May 31.

A diet-induced animal model of non-alcoholic fatty liver disease and hepatocellular cancer.

Author information

1
Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298-0341, USA.
2
Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298-0341, USA. Electronic address: sophie.cazanave@vcuhealth.org.
3
Department of Pathology, Hospital Beaujon, University Paris-Diderot, Paris, France.
4
Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
5
Gene Arrays, Entity of Vedic Research, Inc, New York, NY 11783, USA.
6
Department of Pharmacotherapy and Outcomes Science, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA.
7
Department of Pharmacotherapy and Outcomes Science, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA; Department of Surgery, Virginia Commonwealth University, Richmond, VA 23298, USA.
8
Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298-0341, USA. Electronic address: arun.sanyal@vcuhealth.org.

Abstract

BACKGROUND & AIMS:

The lack of a preclinical model of progressive non-alcoholic steatohepatitis (NASH) that recapitulates human disease is a barrier to therapeutic development.

METHODS:

A stable isogenic cross between C57BL/6J (B6) and 129S1/SvImJ (S129) mice were fed a high fat diet with ad libitum consumption of glucose and fructose in physiologically relevant concentrations and compared to mice fed a chow diet and also to both parent strains.

RESULTS:

Following initiation of the obesogenic diet, B6/129 mice developed obesity, insulin resistance, hypertriglyceridemia and increased LDL-cholesterol. They sequentially also developed steatosis (4-8weeks), steatohepatitis (16-24weeks), progressive fibrosis (16weeks onwards) and spontaneous hepatocellular cancer (HCC). There was a strong concordance between the pattern of pathway activation at a transcriptomic level between humans and mice with similar histological phenotypes (FDR 0.02 for early and 0.08 for late time points). Lipogenic, inflammatory and apoptotic signaling pathways activated in human NASH were also activated in these mice. The HCC gene signature resembled the S1 and S2 human subclasses of HCC (FDR 0.01 for both). Only the B6/129 mouse but not the parent strains recapitulated all of these aspects of human NAFLD.

CONCLUSIONS:

We here describe a diet-induced animal model of non-alcoholic fatty liver disease (DIAMOND) that recapitulates the key physiological, metabolic, histologic, transcriptomic and cell-signaling changes seen in humans with progressive NASH.

LAY SUMMARY:

We have developed a diet-induced mouse model of non-alcoholic steatohepatitis (NASH) and hepatic cancers in a cross between two mouse strains (129S1/SvImJ and C57Bl/6J). This model mimics all the physiological, metabolic, histological, transcriptomic gene signature and clinical endpoints of human NASH and can facilitate preclinical development of therapeutic targets for NASH.

KEYWORDS:

Drug therapy; Fibrosis; Hepatocellular carcinoma; Hepatocyte ballooning; Steatosis

PMID:
27261415
PMCID:
PMC5012902
DOI:
10.1016/j.jhep.2016.05.005
[Indexed for MEDLINE]
Free PMC Article

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