In Silico Modeling of Liver Metabolism in a Human Disease Reveals a Key Enzyme for Histidine and Histamine Homeostasis

Primary hyperoxaluria type I (PH1) is an autosomal-recessive inborn error of liver metabolism caused by alanine:glyoxylate aminotransferase (AGT) deficiency. In silico modeling of liver metabolism in PH1 recapitulated accumulation of known biomarkers as well as alteration of histidine and histamine...

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Main Authors: Roberto Pagliarini, Raffaele Castello, Francesco Napolitano, Roberta Borzone, Patrizia Annunziata, Giorgia Mandrile, Mario De Marchi, Nicola Brunetti-Pierri, Diego di Bernardo
Format: Article
Language:English
Published: Elsevier 2016-06-01
Series:Cell Reports
Online Access:http://www.sciencedirect.com/science/article/pii/S2211124716305812
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spelling doaj-687caa9ce52c4a18a22ed34bf3a633332020-11-25T01:13:26ZengElsevierCell Reports2211-12472016-06-0115102292230010.1016/j.celrep.2016.05.014In Silico Modeling of Liver Metabolism in a Human Disease Reveals a Key Enzyme for Histidine and Histamine HomeostasisRoberto Pagliarini0Raffaele Castello1Francesco Napolitano2Roberta Borzone3Patrizia Annunziata4Giorgia Mandrile5Mario De Marchi6Nicola Brunetti-Pierri7Diego di Bernardo8Telethon Institute of Genetics and Medicine, 80078 Pozzuoli, ItalyTelethon Institute of Genetics and Medicine, 80078 Pozzuoli, ItalyTelethon Institute of Genetics and Medicine, 80078 Pozzuoli, ItalyTelethon Institute of Genetics and Medicine, 80078 Pozzuoli, ItalyTelethon Institute of Genetics and Medicine, 80078 Pozzuoli, ItalyMedical Genetics, San Luigi University Hospital, 10043 Orbassano, ItalyMedical Genetics, San Luigi University Hospital, 10043 Orbassano, ItalyTelethon Institute of Genetics and Medicine, 80078 Pozzuoli, ItalyTelethon Institute of Genetics and Medicine, 80078 Pozzuoli, ItalyPrimary hyperoxaluria type I (PH1) is an autosomal-recessive inborn error of liver metabolism caused by alanine:glyoxylate aminotransferase (AGT) deficiency. In silico modeling of liver metabolism in PH1 recapitulated accumulation of known biomarkers as well as alteration of histidine and histamine levels, which we confirmed in vitro, in vivo, and in PH1 patients. AGT-deficient mice showed decreased vascular permeability, a readout of in vivo histamine activity. Histamine reduction is most likely caused by increased catabolism of the histamine precursor histidine, triggered by rerouting of alanine flux from AGT to the glutamic-pyruvate transaminase (GPT, also known as the alanine-transaminase ALT). Alanine administration reduces histamine levels in wild-type mice, while overexpression of GPT in PH1 mice increases plasma histidine, normalizes histamine levels, restores vascular permeability, and decreases urinary oxalate levels. Our work demonstrates that genome-scale metabolic models are clinically relevant and can link genotype to phenotype in metabolic disorders.http://www.sciencedirect.com/science/article/pii/S2211124716305812
collection DOAJ
language English
format Article
sources DOAJ
author Roberto Pagliarini
Raffaele Castello
Francesco Napolitano
Roberta Borzone
Patrizia Annunziata
Giorgia Mandrile
Mario De Marchi
Nicola Brunetti-Pierri
Diego di Bernardo
spellingShingle Roberto Pagliarini
Raffaele Castello
Francesco Napolitano
Roberta Borzone
Patrizia Annunziata
Giorgia Mandrile
Mario De Marchi
Nicola Brunetti-Pierri
Diego di Bernardo
In Silico Modeling of Liver Metabolism in a Human Disease Reveals a Key Enzyme for Histidine and Histamine Homeostasis
Cell Reports
author_facet Roberto Pagliarini
Raffaele Castello
Francesco Napolitano
Roberta Borzone
Patrizia Annunziata
Giorgia Mandrile
Mario De Marchi
Nicola Brunetti-Pierri
Diego di Bernardo
author_sort Roberto Pagliarini
title In Silico Modeling of Liver Metabolism in a Human Disease Reveals a Key Enzyme for Histidine and Histamine Homeostasis
title_short In Silico Modeling of Liver Metabolism in a Human Disease Reveals a Key Enzyme for Histidine and Histamine Homeostasis
title_full In Silico Modeling of Liver Metabolism in a Human Disease Reveals a Key Enzyme for Histidine and Histamine Homeostasis
title_fullStr In Silico Modeling of Liver Metabolism in a Human Disease Reveals a Key Enzyme for Histidine and Histamine Homeostasis
title_full_unstemmed In Silico Modeling of Liver Metabolism in a Human Disease Reveals a Key Enzyme for Histidine and Histamine Homeostasis
title_sort in silico modeling of liver metabolism in a human disease reveals a key enzyme for histidine and histamine homeostasis
publisher Elsevier
series Cell Reports
issn 2211-1247
publishDate 2016-06-01
description Primary hyperoxaluria type I (PH1) is an autosomal-recessive inborn error of liver metabolism caused by alanine:glyoxylate aminotransferase (AGT) deficiency. In silico modeling of liver metabolism in PH1 recapitulated accumulation of known biomarkers as well as alteration of histidine and histamine levels, which we confirmed in vitro, in vivo, and in PH1 patients. AGT-deficient mice showed decreased vascular permeability, a readout of in vivo histamine activity. Histamine reduction is most likely caused by increased catabolism of the histamine precursor histidine, triggered by rerouting of alanine flux from AGT to the glutamic-pyruvate transaminase (GPT, also known as the alanine-transaminase ALT). Alanine administration reduces histamine levels in wild-type mice, while overexpression of GPT in PH1 mice increases plasma histidine, normalizes histamine levels, restores vascular permeability, and decreases urinary oxalate levels. Our work demonstrates that genome-scale metabolic models are clinically relevant and can link genotype to phenotype in metabolic disorders.
url http://www.sciencedirect.com/science/article/pii/S2211124716305812
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