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

Authors: Pagliarini, Roberto  Castello, Raffaele  Napolitano, Francesco  Borzone, Roberta  Annunziata, Patrizia  Mandrile, Giorgia  De Marchi, Mario  Brunetti-Pierri, Nicola  di Bernardo, Diego 
Citation: Pagliarini R, etal., Cell Rep. 2016 Jun 7;15(10):2292-2300. doi: 10.1016/j.celrep.2016.05.014. Epub 2016 May 26.
Pubmed: (View Article at PubMed) PMID:27239044
DOI: Full-text: DOI:10.1016/j.celrep.2016.05.014

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.

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CRRD Object Information
CRRD ID: 13782155
Created: 2018-08-23
Species: All species
Last Modified: 2018-08-23
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.