Abstract
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.
Highlights
Metabolism is primarily or secondarily affected in several acquired and inherited human diseases
Inborn errors of metabolism (IEMs) are a group of Mendelian disorders resulting from genetic disruption of single metabolic enzymes
We correctly identified metabolites known to accumulate in primary hyperoxaluria type 1 (PH1), such as glyoxylate, glycolate, and oxalate, and discovered a link between AGT and the metabolism of histidine and histamine
Summary
Metabolism is primarily or secondarily affected in several acquired and inherited human diseases. Inborn errors of metabolism (IEMs) are a group of Mendelian disorders resulting from genetic disruption of single metabolic enzymes. A large number of these reactions occurs in the liver. The study of these disorders has been instrumental to understanding the physiological consequences of metabolic reactions and pathogenesis of more common multifactorial diseases. In contrast to Mendelian diseases, which are due to severe impairment of single-enzyme reactions, common multifactorial diseases may result from mild impairment of several metabolic reactions (Lanpher et al, 2006). Our understanding of the consequences of single-enzyme deficiencies on metabolism as a whole are underappreciated, since most studies have been narrowly focused on the affected metabolic reactions, neglecting alterations of more distant metabolites. In most patients affected with IEMs, there are few therapeutic options that are often limited to common sense interventions aimed at either reducing the substrate or increasing the product of the affected reaction
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