A diet-induced animal model of non-alcoholic fatty liver disease and hepatocellular cancer.
The lack of a preclinical model of progressive non-alcoholic steatohepatitis (NASH) that recapitulates human disease is a barrier to therapeutic development.



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.



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.



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.



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.
Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298-0341, USA.
Amon
A
Asgharpour
Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298-0341, USA. Electronic address: sophie.cazanave@vcuhealth.org.
Sophie C
SC
Cazanave
Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298-0341, USA.
Tommy
T
Pacana
Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298-0341, USA.
Mulugeta
M
Seneshaw
Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298-0341, USA.
Robert
R
Vincent
Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298-0341, USA.
Bubu A
BA
Banini
Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298-0341, USA.
Divya Prasanna
DP
Kumar
Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298-0341, USA.
Kalyani
K
Daita
Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298-0341, USA.
Hae-Ki
HK
Min
Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298-0341, USA.
Faridoddin
F
Mirshahi
Department of Pathology, Hospital Beaujon, University Paris-Diderot, Paris, France.
Pierre
P
Bedossa
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.
Xiaochen
X
Sun
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.
Yujin
Y
Hoshida
Gene Arrays, Entity of Vedic Research, Inc, New York, NY 11783, USA.
Srinivas V
SV
Koduru
Department of Pharmacotherapy and Outcomes Science, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA.
Daniel
D
Contaifer
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.
Urszula Osinska
UO
Warncke
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.
Dayanjan S
DS
Wijesinghe
Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298-0341, USA. Electronic address: arun.sanyal@vcuhealth.org.
Arun J
AJ
Sanyal
D000818:Animals; D006528:Carcinoma, Hepatocellular; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D006801:Humans; D008099:Liver; D008113:Liver Neoplasms; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease
Drug therapy; Fibrosis; Hepatocellular carcinoma; Hepatocyte ballooning; Steatosis