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

Amon Asgharpour, Sophie C. Cazanave, Tommy Pacana, Mulugeta Seneshaw, Robert Vincent, Bubu A. Banini, Divya Prasanna Kumar, Kalyani Daita, Hae Ki Min, Faridoddin Mirshahi, Pierre Bedossa, Xiaochen Sun, Yujin Hoshida, Srinivas Koduru, Daniel Contaifer, Urszula Osinska Warncke, Dayanjan S. Wijesinghe, Arun J. Sanyal

Research output: Contribution to journalArticle

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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 (4–8 weeks), steatohepatitis (16–24 weeks), progressive fibrosis (16 weeks 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.

Original languageEnglish (US)
Pages (from-to)579-588
Number of pages10
JournalJournal of Hepatology
Volume65
Issue number3
DOIs
StatePublished - Sep 1 2016

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Fatty Liver
Liver Neoplasms
Animal Models
Diet
129 Strain Mouse
Hypertriglyceridemia
Neoplasm Genes
High Fat Diet
Non-alcoholic Fatty Liver Disease
Fructose
LDL Cholesterol
Insulin Resistance
Fibrosis
Obesity
Phenotype
Glucose
Therapeutics
Genes

All Science Journal Classification (ASJC) codes

  • Hepatology

Cite this

Asgharpour, A., Cazanave, S. C., Pacana, T., Seneshaw, M., Vincent, R., Banini, B. A., ... Sanyal, A. J. (2016). A diet-induced animal model of non-alcoholic fatty liver disease and hepatocellular cancer. Journal of Hepatology, 65(3), 579-588. https://doi.org/10.1016/j.jhep.2016.05.005
Asgharpour, Amon ; Cazanave, Sophie C. ; Pacana, Tommy ; Seneshaw, Mulugeta ; Vincent, Robert ; Banini, Bubu A. ; Kumar, Divya Prasanna ; Daita, Kalyani ; Min, Hae Ki ; Mirshahi, Faridoddin ; Bedossa, Pierre ; Sun, Xiaochen ; Hoshida, Yujin ; Koduru, Srinivas ; Contaifer, Daniel ; Warncke, Urszula Osinska ; Wijesinghe, Dayanjan S. ; Sanyal, Arun J. / A diet-induced animal model of non-alcoholic fatty liver disease and hepatocellular cancer. In: Journal of Hepatology. 2016 ; Vol. 65, No. 3. pp. 579-588.
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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 (4–8 weeks), steatohepatitis (16–24 weeks), progressive fibrosis (16 weeks 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.",
author = "Amon Asgharpour and Cazanave, {Sophie C.} and Tommy Pacana and Mulugeta Seneshaw and Robert Vincent and Banini, {Bubu A.} and Kumar, {Divya Prasanna} and Kalyani Daita and Min, {Hae Ki} and Faridoddin Mirshahi and Pierre Bedossa and Xiaochen Sun and Yujin Hoshida and Srinivas Koduru and Daniel Contaifer and Warncke, {Urszula Osinska} and Wijesinghe, {Dayanjan S.} and Sanyal, {Arun J.}",
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Asgharpour, A, Cazanave, SC, Pacana, T, Seneshaw, M, Vincent, R, Banini, BA, Kumar, DP, Daita, K, Min, HK, Mirshahi, F, Bedossa, P, Sun, X, Hoshida, Y, Koduru, S, Contaifer, D, Warncke, UO, Wijesinghe, DS & Sanyal, AJ 2016, 'A diet-induced animal model of non-alcoholic fatty liver disease and hepatocellular cancer', Journal of Hepatology, vol. 65, no. 3, pp. 579-588. https://doi.org/10.1016/j.jhep.2016.05.005

A diet-induced animal model of non-alcoholic fatty liver disease and hepatocellular cancer. / Asgharpour, Amon; Cazanave, Sophie C.; Pacana, Tommy; Seneshaw, Mulugeta; Vincent, Robert; Banini, Bubu A.; Kumar, Divya Prasanna; Daita, Kalyani; Min, Hae Ki; Mirshahi, Faridoddin; Bedossa, Pierre; Sun, Xiaochen; Hoshida, Yujin; Koduru, Srinivas; Contaifer, Daniel; Warncke, Urszula Osinska; Wijesinghe, Dayanjan S.; Sanyal, Arun J.

In: Journal of Hepatology, Vol. 65, No. 3, 01.09.2016, p. 579-588.

Research output: Contribution to journalArticle

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T1 - A diet-induced animal model of non-alcoholic fatty liver disease and hepatocellular cancer

AU - Asgharpour, Amon

AU - Cazanave, Sophie C.

AU - Pacana, Tommy

AU - Seneshaw, Mulugeta

AU - Vincent, Robert

AU - Banini, Bubu A.

AU - Kumar, Divya Prasanna

AU - Daita, Kalyani

AU - Min, Hae Ki

AU - Mirshahi, Faridoddin

AU - Bedossa, Pierre

AU - Sun, Xiaochen

AU - Hoshida, Yujin

AU - Koduru, Srinivas

AU - Contaifer, Daniel

AU - Warncke, Urszula Osinska

AU - Wijesinghe, Dayanjan S.

AU - Sanyal, Arun J.

PY - 2016/9/1

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N2 - 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 (4–8 weeks), steatohepatitis (16–24 weeks), progressive fibrosis (16 weeks 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.

AB - 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 (4–8 weeks), steatohepatitis (16–24 weeks), progressive fibrosis (16 weeks 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.

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Asgharpour A, Cazanave SC, Pacana T, Seneshaw M, Vincent R, Banini BA et al. A diet-induced animal model of non-alcoholic fatty liver disease and hepatocellular cancer. Journal of Hepatology. 2016 Sep 1;65(3):579-588. https://doi.org/10.1016/j.jhep.2016.05.005