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Comparative Analysis and Modeling of the Severity of Steatohepatitis in DDC-Treated Mouse Strains

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) has a broad spectrum of disease states ranging from mild steatosis characterized by an abnormal retention of lipids within liver cells to steatohepatitis (NASH) showing fat accumulation, inflammation, ballooning and degradation of hepatocytes, an...

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Autores principales: Pandey, Vikash, Sultan, Marc, Kashofer, Karl, Ralser, Meryem, Amstislavskiy, Vyacheslav, Starmann, Julia, Osprian, Ingrid, Grimm, Christina, Hache, Hendrik, Yaspo, Marie-Laure, Sültmann, Holger, Trauner, Michael, Denk, Helmut, Zatloukal, Kurt, Lehrach, Hans, Wierling, Christoph
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4210132/
https://www.ncbi.nlm.nih.gov/pubmed/25347188
http://dx.doi.org/10.1371/journal.pone.0111006
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author Pandey, Vikash
Sultan, Marc
Kashofer, Karl
Ralser, Meryem
Amstislavskiy, Vyacheslav
Starmann, Julia
Osprian, Ingrid
Grimm, Christina
Hache, Hendrik
Yaspo, Marie-Laure
Sültmann, Holger
Trauner, Michael
Denk, Helmut
Zatloukal, Kurt
Lehrach, Hans
Wierling, Christoph
author_facet Pandey, Vikash
Sultan, Marc
Kashofer, Karl
Ralser, Meryem
Amstislavskiy, Vyacheslav
Starmann, Julia
Osprian, Ingrid
Grimm, Christina
Hache, Hendrik
Yaspo, Marie-Laure
Sültmann, Holger
Trauner, Michael
Denk, Helmut
Zatloukal, Kurt
Lehrach, Hans
Wierling, Christoph
author_sort Pandey, Vikash
collection PubMed
description BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) has a broad spectrum of disease states ranging from mild steatosis characterized by an abnormal retention of lipids within liver cells to steatohepatitis (NASH) showing fat accumulation, inflammation, ballooning and degradation of hepatocytes, and fibrosis. Ultimately, steatohepatitis can result in liver cirrhosis and hepatocellular carcinoma. METHODOLOGY AND RESULTS: In this study we have analyzed three different mouse strains, A/J, C57BL/6J, and PWD/PhJ, that show different degrees of steatohepatitis when administered a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) containing diet. RNA-Seq gene expression analysis, protein analysis and metabolic profiling were applied to identify differentially expressed genes/proteins and perturbed metabolite levels of mouse liver samples upon DDC-treatment. Pathway analysis revealed alteration of arachidonic acid (AA) and S-adenosylmethionine (SAMe) metabolism upon other pathways. To understand metabolic changes of arachidonic acid metabolism in the light of disease expression profiles a kinetic model of this pathway was developed and optimized according to metabolite levels. Subsequently, the model was used to study in silico effects of potential drug targets for steatohepatitis. CONCLUSIONS: We identified AA/eicosanoid metabolism as highly perturbed in DDC-induced mice using a combination of an experimental and in silico approach. Our analysis of the AA/eicosanoid metabolic pathway suggests that 5-hydroxyeicosatetraenoic acid (5-HETE), 15-hydroxyeicosatetraenoic acid (15-HETE) and prostaglandin D2 (PGD2) are perturbed in DDC mice. We further demonstrate that a dynamic model can be used for qualitative prediction of metabolic changes based on transcriptomics data in a disease-related context. Furthermore, SAMe metabolism was identified as being perturbed due to DDC treatment. Several genes as well as some metabolites of this module show differences between A/J and C57BL/6J on the one hand and PWD/PhJ on the other.
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spelling pubmed-42101322014-10-30 Comparative Analysis and Modeling of the Severity of Steatohepatitis in DDC-Treated Mouse Strains Pandey, Vikash Sultan, Marc Kashofer, Karl Ralser, Meryem Amstislavskiy, Vyacheslav Starmann, Julia Osprian, Ingrid Grimm, Christina Hache, Hendrik Yaspo, Marie-Laure Sültmann, Holger Trauner, Michael Denk, Helmut Zatloukal, Kurt Lehrach, Hans Wierling, Christoph PLoS One Research Article BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) has a broad spectrum of disease states ranging from mild steatosis characterized by an abnormal retention of lipids within liver cells to steatohepatitis (NASH) showing fat accumulation, inflammation, ballooning and degradation of hepatocytes, and fibrosis. Ultimately, steatohepatitis can result in liver cirrhosis and hepatocellular carcinoma. METHODOLOGY AND RESULTS: In this study we have analyzed three different mouse strains, A/J, C57BL/6J, and PWD/PhJ, that show different degrees of steatohepatitis when administered a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) containing diet. RNA-Seq gene expression analysis, protein analysis and metabolic profiling were applied to identify differentially expressed genes/proteins and perturbed metabolite levels of mouse liver samples upon DDC-treatment. Pathway analysis revealed alteration of arachidonic acid (AA) and S-adenosylmethionine (SAMe) metabolism upon other pathways. To understand metabolic changes of arachidonic acid metabolism in the light of disease expression profiles a kinetic model of this pathway was developed and optimized according to metabolite levels. Subsequently, the model was used to study in silico effects of potential drug targets for steatohepatitis. CONCLUSIONS: We identified AA/eicosanoid metabolism as highly perturbed in DDC-induced mice using a combination of an experimental and in silico approach. Our analysis of the AA/eicosanoid metabolic pathway suggests that 5-hydroxyeicosatetraenoic acid (5-HETE), 15-hydroxyeicosatetraenoic acid (15-HETE) and prostaglandin D2 (PGD2) are perturbed in DDC mice. We further demonstrate that a dynamic model can be used for qualitative prediction of metabolic changes based on transcriptomics data in a disease-related context. Furthermore, SAMe metabolism was identified as being perturbed due to DDC treatment. Several genes as well as some metabolites of this module show differences between A/J and C57BL/6J on the one hand and PWD/PhJ on the other. Public Library of Science 2014-10-27 /pmc/articles/PMC4210132/ /pubmed/25347188 http://dx.doi.org/10.1371/journal.pone.0111006 Text en © 2014 Pandey et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Pandey, Vikash
Sultan, Marc
Kashofer, Karl
Ralser, Meryem
Amstislavskiy, Vyacheslav
Starmann, Julia
Osprian, Ingrid
Grimm, Christina
Hache, Hendrik
Yaspo, Marie-Laure
Sültmann, Holger
Trauner, Michael
Denk, Helmut
Zatloukal, Kurt
Lehrach, Hans
Wierling, Christoph
Comparative Analysis and Modeling of the Severity of Steatohepatitis in DDC-Treated Mouse Strains
title Comparative Analysis and Modeling of the Severity of Steatohepatitis in DDC-Treated Mouse Strains
title_full Comparative Analysis and Modeling of the Severity of Steatohepatitis in DDC-Treated Mouse Strains
title_fullStr Comparative Analysis and Modeling of the Severity of Steatohepatitis in DDC-Treated Mouse Strains
title_full_unstemmed Comparative Analysis and Modeling of the Severity of Steatohepatitis in DDC-Treated Mouse Strains
title_short Comparative Analysis and Modeling of the Severity of Steatohepatitis in DDC-Treated Mouse Strains
title_sort comparative analysis and modeling of the severity of steatohepatitis in ddc-treated mouse strains
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4210132/
https://www.ncbi.nlm.nih.gov/pubmed/25347188
http://dx.doi.org/10.1371/journal.pone.0111006
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