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Cell Rep. 2016 Jun 7;15(10):2292-2300. doi: 10.1016/j.celrep.2016.05.014. Epub 2016 May 26.

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

Author information

1
Telethon Institute of Genetics and Medicine, 80078 Pozzuoli, Italy.
2
Medical Genetics, San Luigi University Hospital, 10043 Orbassano, Italy; Department of Clinical & Biological Sciences, University of Turin, 10043 Orbassano, Italy.
3
Telethon Institute of Genetics and Medicine, 80078 Pozzuoli, Italy; Department of Translational Medicine, Federico II University, 80131 Naples, Italy. Electronic address: brunetti@tigem.it.
4
Telethon Institute of Genetics and Medicine, 80078 Pozzuoli, Italy; Department of Chemical, Materials and Industrial Engineering, Federico II University, 80125 Naples, Italy. Electronic address: dibernardo@tigem.it.

Abstract

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.

PMID:
27239044
PMCID:
PMC4906368
DOI:
10.1016/j.celrep.2016.05.014
[Indexed for MEDLINE]
Free PMC Article

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