کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2039204 1073034 2016 9 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
In Silico Modeling of Liver Metabolism in a Human Disease Reveals a Key Enzyme for Histidine and Histamine Homeostasis
ترجمه فارسی عنوان
در سیلیکو مدلسازی متابولیسم کبدی در یک بیماری انسانی یک آنزیم کلیدی برای هیستاتین و هیستامین هیستاماتوز را نشان می دهد
موضوعات مرتبط
علوم زیستی و بیوفناوری علوم کشاورزی و بیولوژیک علوم کشاورزی و بیولوژیک (عمومی)
چکیده انگلیسی


• In silico model of liver metabolism reveals global metabolic alterations in PH1
• Changes in amino acid metabolism in PH1 result in a reduction of histidine and histamine
• GPT overexpression normalizes histamine levels and reduces oxalate in PH1 mice

SummaryPrimary 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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ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: - Volume 15, Issue 10, 7 June 2016, Pages 2292–2300
نویسندگان
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