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• Hoppe, A
• Ilkavets, I
• Dooley, S
• Holzhütter, H
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• Hoppe, A
• Ilkavets, I
• Dooley, S
• Holzhütter, H
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• Hoppe, A
• Ilkavets, I
• Dooley, S
• Holzhütter, H

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Metabolites 2012, 2(4), 983-1003; doi:10.3390/metabo2040983

Article

Metabolic Consequences of TGFb Stimulation in CulturedPrimary Mouse Hepatocytes Screened from Transcript Data with ModeScore 

Andreas Hoppe ^1,* , Iryna Ilkavets ² , Steven Dooley ²  and Hermann-Georg Holzhütter ¹

¹ Institute for Biochemistry, Charité University Medicine Berlin, Charitéplatz 1/Virchowweg 6, 10117 Berlin, Germany ² Molecular Hepatology and Alcohol Associated Diseases, Medical Clinic II, Medical Faculty Mannheim at Heidelberg University, Theodor-Kutzer-Ufer 1-3, H42 E4, 68167 Mannheim, Germany

* Author to whom correspondence should be addressed.

Received: 29 August 2012; in revised form: 18 October 2012 / Accepted: 7 November 2012 / Published: 21 November 2012

(This article belongs to the Special Issue Metabolic Network Models)

Download PDF Full-Text [1195 KB, Updated Version, uploaded 10 December 2012 13:59 CET]

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Abstract: TGFb signaling plays a major role in the reorganization of liver tissue upon injury and is an important driver of chronic liver disease. This is achieved by a deep impact on a cohort of cellular functions. To comprehensively assess the full range of affected metabolic functions, transcript changes of cultured mouse hepatocytes were analyzed with a novel method (ModeScore), which predicts the activity of metabolic functions by scoring transcript expression changes with 987 reference flux distributions, which yielded the following hypotheses. TGFb multiplies down-regulation of most metabolic functions occurring in culture stressed controls. This is especially pronounced for tyrosine degradation, urea synthesis, glucuronization capacity, and cholesterol synthesis. Ethanol degradation and creatine synthesis are down-regulated only in TGFb treated hepatocytes, but not in the control. Among the few TGFb dependently up-regulated functions, synthesis of various collagens is most pronounced. Further interesting findings include: down-regulation of glucose export is postponed by TGFb, TGFb up-regulates the synthesis capacity of ketone bodies only as an early response, TGFb suppresses the strong up-regulation of Vanin, and TGFb induces re-formation of ceramides and sphingomyelin.

Keywords: hepatocyte; transforming growth factor beta; transcriptomics; metabolic network; VirtualLiver Network

Supplementary Files

• Supplementary File 1:

  Complete account of the selection process (PDF, 2112 KB)

• Supplementary File 2:

  Supplemental File (ZIP, 168 KB)

• Supplementary File 3:

  Definition of the simulations and solution summary (PDF, 792 KB)

• Supplementary File 4:

  Solutions (PDF, 3957 KB)

• Supplementary File 5:

  Scores and amplitudes tables (PDF, 994 KB)

• Supplementary File 6:

  Detailed reaction scores (PDF, 617 KB)

• Supplementary File 7:

  Setting of the weights (PDF, 80 KB)

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