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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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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