Cargando…
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...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cell Press
2016
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4906368/ https://www.ncbi.nlm.nih.gov/pubmed/27239044 http://dx.doi.org/10.1016/j.celrep.2016.05.014 |
_version_ | 1782437407645237248 |
---|---|
author | Pagliarini, Roberto Castello, Raffaele Napolitano, Francesco Borzone, Roberta Annunziata, Patrizia Mandrile, Giorgia De Marchi, Mario Brunetti-Pierri, Nicola di Bernardo, Diego |
author_facet | Pagliarini, Roberto Castello, Raffaele Napolitano, Francesco Borzone, Roberta Annunziata, Patrizia Mandrile, Giorgia De Marchi, Mario Brunetti-Pierri, Nicola di Bernardo, Diego |
author_sort | Pagliarini, Roberto |
collection | PubMed |
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. |
format | Online Article Text |
id | pubmed-4906368 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Cell Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-49063682016-06-22 In Silico Modeling of Liver Metabolism in a Human Disease Reveals a Key Enzyme for Histidine and Histamine Homeostasis Pagliarini, Roberto Castello, Raffaele Napolitano, Francesco Borzone, Roberta Annunziata, Patrizia Mandrile, Giorgia De Marchi, Mario Brunetti-Pierri, Nicola di Bernardo, Diego Cell Rep Resource 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. Cell Press 2016-05-26 /pmc/articles/PMC4906368/ /pubmed/27239044 http://dx.doi.org/10.1016/j.celrep.2016.05.014 Text en © 2016 The Author(s) http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Resource Pagliarini, Roberto Castello, Raffaele Napolitano, Francesco Borzone, Roberta Annunziata, Patrizia Mandrile, Giorgia De Marchi, Mario Brunetti-Pierri, Nicola di Bernardo, Diego In Silico Modeling of Liver Metabolism in a Human Disease Reveals a Key Enzyme for Histidine and Histamine Homeostasis |
title | 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_short | 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 |
topic | Resource |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4906368/ https://www.ncbi.nlm.nih.gov/pubmed/27239044 http://dx.doi.org/10.1016/j.celrep.2016.05.014 |
work_keys_str_mv | AT pagliariniroberto insilicomodelingoflivermetabolisminahumandiseaserevealsakeyenzymeforhistidineandhistaminehomeostasis AT castelloraffaele insilicomodelingoflivermetabolisminahumandiseaserevealsakeyenzymeforhistidineandhistaminehomeostasis AT napolitanofrancesco insilicomodelingoflivermetabolisminahumandiseaserevealsakeyenzymeforhistidineandhistaminehomeostasis AT borzoneroberta insilicomodelingoflivermetabolisminahumandiseaserevealsakeyenzymeforhistidineandhistaminehomeostasis AT annunziatapatrizia insilicomodelingoflivermetabolisminahumandiseaserevealsakeyenzymeforhistidineandhistaminehomeostasis AT mandrilegiorgia insilicomodelingoflivermetabolisminahumandiseaserevealsakeyenzymeforhistidineandhistaminehomeostasis AT demarchimario insilicomodelingoflivermetabolisminahumandiseaserevealsakeyenzymeforhistidineandhistaminehomeostasis AT brunettipierrinicola insilicomodelingoflivermetabolisminahumandiseaserevealsakeyenzymeforhistidineandhistaminehomeostasis AT dibernardodiego insilicomodelingoflivermetabolisminahumandiseaserevealsakeyenzymeforhistidineandhistaminehomeostasis |