Hyperammonemia induces programmed liver cell death
Science Advances, vol. 11, pp. eado1648
Abstract
Hyperammonemia is common in liver cirrhosis and causally associated with hepatic encephalopathy development. Little is known about its hepatotoxic effects, which we aimed to characterize in this study. In a mouse model of chronic hyperammonemia without preexisting liver disease, we observed development of liver fibrogenesis and necroptotic cell death. Hyperammonemia also induced dysregulation of its main metabolic pathway, the urea cycle, as reflected by down-regulation of urea cycle enzyme protein expression and accumulation of its metabolites. Inhibition of receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and its upstream inducer Toll-like receptor 4 (TLR4) protected against liver injury and further hyperammonemia. In clinically relevant rodent models of hyperammonemia (genetic ornithine transcarbamylase deficiency and bile duct ligation-induced cirrhosis), TLR4 inhibition reduced circulating ammonia. In conclusion, hyperammonemia induces liver fibrogenesis and RIPK1-mediated cell death, which is associated with urea cycle dysfunction. Inhibition of RIPK1 and TLR4 protects against hyperammonemia-induced liver injury and are potential therapeutic targets for hyperammonemia and chronic liver disease progression.
Authors 24
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Leiden University Medical Center · The Royal Free Hospital · University College London
Affiliation as printed
Department of Gastroenterology & Hepatology, Leiden University Medical Center, Leiden, Netherlands
Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK
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The Royal Free Hospital · University College London · Charité - Universitätsmedizin Berlin
Affiliation as printed
Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK
Medical Department, Division of Hepatology and Gastroenterology, Campus Virchow-Klinikum, Charite - Universitätsmedizin Berlin, Berlin, Germany
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The Royal Free Hospital · University College London
Affiliation as printed
Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK
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Charité - Universitätsmedizin Berlin
Affiliation as printed
Medical Department, Division of Hepatology and Gastroenterology, Campus Virchow-Klinikum, Charite - Universitätsmedizin Berlin, Berlin, Germany
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Boehringer Ingelheim (Germany) · Charité - Universitätsmedizin Berlin
Affiliation as printed
Department of CardioMetabolic Disease Research, Boehringer Ingelheim, Biberach, Germany
Medical Department, Division of Hepatology and Gastroenterology, Campus Virchow-Klinikum, Charite - Universitätsmedizin Berlin, Berlin, Germany
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The Royal Free Hospital · Nanfang Hospital · University College London · Southern Medical University
Affiliation as printed
Department of Hepatology Unit and Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK
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Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
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Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
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Affiliation as printed
Department of Cellular Pathology, Royal Free Hospital, London, UK
The Sheila Sherlock Liver Centre, Royal Free Hospital, London, UK
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The Royal Free Hospital · University College London
Affiliation as printed
Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK
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Affiliation as printed
Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, Netherlands
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European Foundation for the Study of Chronic Liver Failure
Affiliation as printed
European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain
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Commissariat à l'Énergie Atomique et aux Énergies Alternatives · Université Paris-Saclay · Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement · CEA Paris-Saclay · MetaboHUB · Médicaments et Technologies pour la Santé
Affiliation as printed
Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé (DMTS), MetaboHUB-IDF, 91191 Gif-sur-Yvette, France
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Commissariat à l'Énergie Atomique et aux Énergies Alternatives · Université Paris-Saclay · Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement · CEA Paris-Saclay · MetaboHUB · Médicaments et Technologies pour la Santé
Affiliation as printed
Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé (DMTS), MetaboHUB-IDF, 91191 Gif-sur-Yvette, France
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European Foundation for the Study of Chronic Liver Failure · Hospital Clínic de Barcelona · Consorci Institut D'Investigacions Biomediques August Pi I Sunyer · Universitat de Barcelona
Affiliation as printed
European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain
Hospital Clínic-IDIBAPS, University of Barcelona, Barcelona, Spain
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Inserm · Université Paris Cité · Hôpital Beaujon · Assistance Publique – Hôpitaux de Paris · European Foundation for the Study of Chronic Liver Failure · Centre de Recherche sur l'Inflammation
Affiliation as printed
European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain
Inserm and Université de Paris, Centre de Recherche sur l’Inflammation (CRI), UMRS1149 Paris, France
Service d’Hépatologie, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy, France
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European Foundation for the Study of Chronic Liver Failure
Affiliation as printed
European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain
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Leiden University Medical Center
Affiliation as printed
Department of Gastroenterology & Hepatology, Leiden University Medical Center, Leiden, Netherlands
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The Royal Free Hospital · Foundation for Liver Research · University College London
Affiliation as printed
Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK
The Roger Williams Institute of Hepatology, Foundation for Liver Research, London, UK
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Commissariat à l'Énergie Atomique et aux Énergies Alternatives · Université Paris-Saclay · Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement · CEA Paris-Saclay · MetaboHUB · Médicaments et Technologies pour la Santé
Affiliation as printed
Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé (DMTS), MetaboHUB-IDF, 91191 Gif-sur-Yvette, France
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TU Dortmund University · Universitätsklinikum Aachen · Leibniz Research Centre for Working Environment and Human Factors · RWTH Aachen University
Affiliation as printed
Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
IFADO, Department of Toxicology, TU Dortmund, Dortmund, Germany
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Commissariat à l'Énergie Atomique et aux Énergies Alternatives · Université Paris-Saclay · Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement · CEA Paris-Saclay · MetaboHUB · Médicaments et Technologies pour la Santé
Affiliation as printed
Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé (DMTS), MetaboHUB-IDF, 91191 Gif-sur-Yvette, France
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The Royal Free Hospital · University College London
Affiliation as printed
Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK
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Rajiv Jalan corresponding
The Royal Free Hospital · European Foundation for the Study of Chronic Liver Failure · University College London
Affiliation as printed
European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain
Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK
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