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  Comparative analysis and modeling of the severity of steatohepatitis in DDC-treated mouse strains

Pandey, V., Sultan, M., Kashofer, K., Ralser, M., Amstislavskiy, V., Starmann, J., et al. (2014). Comparative analysis and modeling of the severity of steatohepatitis in DDC-treated mouse strains. PLoS One, 9(10): e111006. doi:10.1371/journal.pone.0111006.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0025-B59E-5 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0025-B5A4-6
Genre: Journal Article

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Pandey, V.1, Author              
Sultan, M.2, Author              
Kashofer, K., Author
Ralser, M.2, Author
Amstislavskiy, V.2, Author              
Starmann, J., Author
Osprian, I., Author
Grimm, C., Author
Hache, H.1, Author              
Yaspo, M. L.3, Author              
Sultmann, H., Author
Trauner, M., Author
Denk, H., Author
Zatloukal, K., Author
Lehrach, H.4, Author              
Wierling, C.1, Author              
Affiliations:
1Systems Biology (Christoph Wierling), Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479656              
2Human Chromosome 21 (Marie-Laure Yaspo), Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479652              
3Gene Regulation and Systems Biology of Cancer (Marie-Laure Yaspo), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2117287              
4Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433550              

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 Abstract: 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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Language(s): eng - English
 Dates: 2014-10-27
 Publication Status: Published online
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 Rev. Type: Peer
 Identifiers: DOI: 10.1371/journal.pone.0111006
ISSN: 1932-6203 (Electronic)
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Title: PLoS One
Source Genre: Journal
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Publ. Info: San Francisco, CA : Public Library of Science
Pages: - Volume / Issue: 9 (10) Sequence Number: e111006 Start / End Page: - Identifier: ISSN: 1932-6203
CoNE: https://pure.mpg.de/cone/journals/resource/1000000000277850