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  A Systems Biology Approach to Deciphering the Etiology of Steatosis Employing Patient-Derived Dermal Fibroblasts and iPS Cells

Jozefczuk, J., Kashofer, K., Ummanni, R., Henjes, F., Rehman, S., Geenen, S., et al. (2012). A Systems Biology Approach to Deciphering the Etiology of Steatosis Employing Patient-Derived Dermal Fibroblasts and iPS Cells. Frontiers in Systems Biology, 3(3): 3:339. doi:10.3389/fphys.2012.00339.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-000E-F055-D Version Permalink: http://hdl.handle.net/11858/00-001M-0000-000E-F056-B
Genre: Journal Article

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© 2012 Jozefczuk, Kashofer, Ummanni, Henjes, Rehman, Geenen, Wruck, Regenbrecht, Daskalaki, Wierling, Turano, Bertini, Korf, Zatloukal, Westerhoff, Lehrach and Adjaye. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.
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 Creators:
Jozefczuk, Justyna1, Author              
Kashofer, Karl2, Author
Ummanni, Ramesh3, Author
Henjes, Frauke3, Author
Rehman, Samrina4, Author
Geenen, Suzanne4, Author
Wruck, Wasco5, Author
Regenbrecht, Chritian5, Author
Daskalaki, Andriani6, Author              
Wierling, Christoph K.6, Author              
Turano, Paola7, Author
Bertini, Ivano7, Author
Korf, Ulrike3, Author
Zatloukal, Kurt2, Author
Westerhoff, Hans V.4, 7, 8, 9, Author
Lehrach, Hans10, Author              
Adjaye, James1, Author              
Affiliations:
1Molecular Embryology and Aging (James Adjaye), Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, Ihnestr. 63-74, Berlin, Germany, ou_1479654              
2Institute of Pathology, Medical University of Graz, Graz, Austria, ou_persistent22              
3Division of Molecular Genome Analysis, German Cancer Research Center, Heidelberg, Germany, ou_persistent22              
4Manchester Centre for Integrative Systems Biology, Manchester Interdisciplinary Biocentre, University of Manchester, Manchester, UK, ou_persistent22              
5Cancer Stem Cell Group, Institute for Pathology and Comprehensive Cancer Center, Charité – Universitätsmedizin, ,Berlin, Germany, ou_persistent22              
6Systems Biology (Christoph Wierling), Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, Ihnestr. 63-74, Berlin, Germany, ou_1479656              
7Magnetic Resonance Center, University of Florence , Florence, Italy, ou_persistent22              
8Doctoral Training Centre ISBML, The Manchester Centre for Integrative Systems Biology, Manchester Interdisciplinary Biocentre, University of Manchester,, Manchester, UK, ou_persistent22              
9Synthetic Systems Biology, Swammerdam Institute for Life Sciences, University of Amsterdam,, Amsterdam, Netherlands, ou_persistent22              
10Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, Ihnestr. 63-74, Berlin, Germany, ou_1433550              

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Free keywords: NAFLD, induced pluripotent stem cells, sterol biosynthesis, glutathione metabolism, lipid metabolism, AKT/mTOR signaling, systems biology, modeling
 Abstract: Non-alcoholic fatty liver disease comprises a broad spectrum of disease states ranging from simple steatosis to non-alcoholic steatohepatitis. As a result of increases in the prevalences of obesity, insulin resistance, and hyperlipidemia, the number of people with hepatic steatosis continues to increase. Differences in susceptibility to steatohepatitis and its progression to cirrhosis have been attributed to a complex interplay of genetic and external factors all addressing the intracellular network. Increase in sugar or refined carbohydrate consumption results in an increase of insulin and insulin resistance that can lead to the accumulation of fat in the liver. Here we demonstrate how a multidisciplinary approach encompassing cellular reprogramming, transcriptomics, proteomics, metabolomics, modeling, network reconstruction, and data management can be employed to unveil the mechanisms underlying the progression of steatosis. Proteomics revealed reduced AKT/mTOR signaling in fibroblasts derived from steatosis patients and further establishes that the insulin-resistant phenotype is present not only in insulin-metabolizing central organs, e.g., the liver, but is also manifested in skin fibroblasts. Transcriptome data enabled the generation of a regulatory network based on the transcription factor SREBF1, linked to a metabolic network of glycerolipid, and fatty acid biosynthesis including the downstream transcriptional targets of SREBF1 which include LIPIN1 (LPIN) and low density lipoprotein receptor. Glutathione metabolism was among the pathways enriched in steatosis patients in comparison to healthy controls. By using a model of the glutathione pathway we predict a significant increase in the flux through glutathione synthesis as both gamma-glutamylcysteine synthetase and glutathione synthetase have an increased flux. We anticipate that a larger cohort of patients and matched controls will confirm our preliminary findings presented here.

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Language(s): eng - English
 Dates: 2012-09-032012
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.3389/fphys.2012.00339
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Title: Frontiers in Systems Biology
Source Genre: Journal
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Publ. Info: Lausanne : Frontiers Research Foundation
Pages: - Volume / Issue: 3 (3) Sequence Number: 3:339 Start / End Page: - Identifier: -