Universität zu Köln

Ghallab, Ahmed ORCID: 0000-0003-0695-3403, Celliere, Geraldine, Henkel, Sebastian G., Driesch, Dominik, Hoehme, Stefan, Hofmann, Ute ORCID: 0000-0003-0823-9027, Zellmer, Sebastian, Godoy, Patricio, Sachinidis, Agapios, Blaszkewicz, Meinolf, Reif, Raymond, Marchan, Rosemarie ORCID: 0000-0003-4414-1633, Kuepfer, Lars ORCID: 0000-0002-8741-7786, Haeussinger, Dieter, Drasdo, Dirk, Gebhardt, Rolf and Hengstler, Jan G. (2016). Model-guided identification of a therapeutic strategy to reduce hyperammonemia in liver diseases. J. Hepatol., 64 (4). S. 860 - 872. AMSTERDAM: ELSEVIER SCIENCE BV. ISSN 1600-0641

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Abstract

Background & Aims: 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 (alpha-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), alpha-KG (280 mg/kg) and NADPH (180 mg/kg) reduced the elevated blood ammonia concentrations (>200 mu M) to levels close to normal within only 15 min. Conclusion: If successfully translated to patients the GDH-based therapy might provide a less aggressive therapeutic alternative for patients with severe hyperammonemia. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Ghallab, Ahmed UNSPECIFIED orcid.org/0000-0003-0695-3403 UNSPECIFIED Celliere, Geraldine UNSPECIFIED UNSPECIFIED UNSPECIFIED Henkel, Sebastian G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Driesch, Dominik UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoehme, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED Hofmann, Ute UNSPECIFIED orcid.org/0000-0003-0823-9027 UNSPECIFIED Zellmer, Sebastian UNSPECIFIED UNSPECIFIED UNSPECIFIED Godoy, Patricio UNSPECIFIED UNSPECIFIED UNSPECIFIED Sachinidis, Agapios UNSPECIFIED UNSPECIFIED UNSPECIFIED Blaszkewicz, Meinolf UNSPECIFIED UNSPECIFIED UNSPECIFIED Reif, Raymond UNSPECIFIED UNSPECIFIED UNSPECIFIED Marchan, Rosemarie UNSPECIFIED orcid.org/0000-0003-4414-1633 UNSPECIFIED Kuepfer, Lars UNSPECIFIED orcid.org/0000-0002-8741-7786 UNSPECIFIED Haeussinger, Dieter UNSPECIFIED UNSPECIFIED UNSPECIFIED Drasdo, Dirk UNSPECIFIED UNSPECIFIED UNSPECIFIED Gebhardt, Rolf UNSPECIFIED UNSPECIFIED UNSPECIFIED Hengstler, Jan G. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-280534
DOI:	10.1016/j.jhep.2015.11.018
Journal or Publication Title:	J. Hepatol.
Volume:	64
Number:	4
Page Range:	S. 860 - 872
Date:	2016
Publisher:	ELSEVIER SCIENCE BV
Place of Publication:	AMSTERDAM
ISSN:	1600-0641
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language HEPATOCYTE HETEROGENEITY; GLUTAMINE-SYNTHETASE; CYCLE; HEMODIALYSIS; HEPATOTOXICITY; PHENYLACETATE; METABOLISM; AMMONIA; SYSTEMS; CELLS Multiple languages Gastroenterology & Hepatology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/28053