title: Model-guided identification of a therapeutic strategy to reduce hyperammonemia in liver diseases.
abstract: OBJECTIVE
  Recently, spatial-temporal/metabolic mathematical models have been established that allow the simulation of metabolic processes in tissues. We applied these models to decipher ammonia detoxification mechanisms in the liver.
  
  
  METHODS
  An integrated metabolic-spatial-temporal model was used to generate hypotheses of ammonia metabolism. Predicted mechanisms were validated using time-resolved analyses of nitrogen metabolism, activity analyses, immunostaining and gene expression after induction of liver damage in mice. Moreover, blood from the portal vein, liver vein and mixed venous blood was analyzed in a time dependent manner.
  
  
  RESULTS
  Modeling revealed an underestimation of ammonia consumption after liver damage when only the currently established mechanisms of ammonia detoxification were simulated. By iterative cycles of modeling and experiments, the reductive amidation of alpha-ketoglutarate (α-KG) via glutamate dehydrogenase (GDH) was identified as the lacking component. GDH is released from damaged hepatocytes into the blood where it consumes ammonia to generate glutamate, thereby providing systemic protection against hyperammonemia. This mechanism was exploited therapeutically in a mouse model of hyperammonemia by injecting GDH together with optimized doses of cofactors. Intravenous injection of GDH (720 U/kg), α-KG (280 mg/kg) and NADPH (180 mg/kg) reduced the elevated blood ammonia concentrations (>200 μM) to levels close to normal within only 15 min.
  
  
  CONCLUSIONS
  If successfully translated to patients the GDH-based therapy might provide a less aggressive therapeutic alternative for patients with severe hyperammonemia.
authors.affiliation: Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany; Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt. Electronic address: ghallab@ifado.de.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Ghallab
authors.affiliation: Sorbonne Universités, Inria, UPMC Univ Paris 06, Lab. J.L. Lions UMR CNRS 7598, Paris, France.
authors.forename: Géraldine
authors.initials: G
authors.lastname: Cellière
authors.affiliation: BioControl Jena GmbH, Jena, Germany.
authors.forename: Sebastian G
authors.initials: SG
authors.lastname: Henkel
authors.affiliation: BioControl Jena GmbH, Jena, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Driesch
authors.affiliation: Institute of Computer Science and Interdisciplinary Centre for Bioinformatics, University of Leipzig, Leipzig, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Hoehme
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and University of Tuebingen, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Hofmann
authors.affiliation: Institute of Biochemistry, Faculty of Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Zellmer
authors.affiliation: Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany.
authors.forename: Patricio
authors.initials: P
authors.lastname: Godoy
authors.affiliation: Institute of Neurophysiology and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Robert-Koch-Str. 39, 50931 Cologne, Germany.
authors.forename: Agapios
authors.initials: A
authors.lastname: Sachinidis
authors.affiliation: Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany.
authors.forename: Meinolf
authors.initials: M
authors.lastname: Blaszkewicz
authors.affiliation: Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany.
authors.forename: Raymond
authors.initials: R
authors.lastname: Reif
authors.affiliation: Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany.
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Marchan
authors.affiliation: Computational Systems Biology, Bayer Technology Services GmbH, Leverkusen, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Kuepfer
authors.affiliation: Clinic for Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Häussinger
authors.affiliation: Sorbonne Universités, Inria, UPMC Univ Paris 06, Lab. J.L. Lions UMR CNRS 7598, Paris, France; Institute of Computer Science and Interdisciplinary Centre for Bioinformatics, University of Leipzig, Leipzig, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Drasdo
authors.affiliation: Institute of Biochemistry, Faculty of Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Gebhardt
authors.affiliation: Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany. Electronic address: hengstler@ifado.de.
authors.forename: Jan G
authors.initials: JG
authors.lastname: Hengstler
mesh_terms: D000818:Animals; D005969:Glutamate Dehydrogenase / Q000502:physiology; D022124:Hyperammonemia / Q000188:drug therapy*; D007656:Ketoglutaric Acids / Q000627:therapeutic use; D008107:Liver Diseases / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D007656:Ketoglutaric Acids; D005969:Glutamate Dehydrogenase
keywords: Ammonia; Liver damage; Liver regeneration; Spatio-temporal model; Systems biology