4.4 Article Proceedings Paper

Comprehensive characterization of ureagenesis in the spfash mouse, a model of human ornithine transcarbamylase deficiency, reveals age-dependency of ammonia detoxification

期刊

JOURNAL OF INHERITED METABOLIC DISEASE
卷 42, 期 6, 页码 1064-1076

出版社

WILEY
DOI: 10.1002/jimd.12068

关键词

age-dependency; gut microbiome; hyperammonemia; ornithine transcarbamylase (OTC) deficiency; spf(ash) mouse model; urea cycle disorders; ureagenesis

资金

  1. Ministry of Health of the Czech Republic [RVO-VFN 64165]
  2. Swiss National Science Foundation
  3. Stiftung fur wissenschaftliche Forschung UZH [SNF 310030_153196, CRSII5-180256, SNF 310030-162547]
  4. Wolfermann Nageli Stiftung
  5. Children's Research Center Zurich

向作者/读者索取更多资源

The most common ureagenesis defect is X-linked ornithine transcarbamylase (OTC) deficiency which is a main target for novel therapeutic interventions. The spf(ash) mouse model carries a variant (c.386G>A, p.Arg129His) that is also found in patients. Male spf(ash) mice have a mild biochemical phenotype with low OTC activity (5%-10% of wild-type), resulting in elevated urinary orotic acid but no hyperammonemia. We recently established a dried blood spot method for in vivo quantification of ureagenesis by Gas chromatography-mass spectrometry (GC-MS) using stable isotopes. Here, we applied this assay to wild-type and spf(ash) mice to assess ureagenesis at different ages. Unexpectedly, we found an age-dependency with a higher capacity for ammonia detoxification in young mice after weaning. A parallel pattern was observed for carbamoylphosphate synthetase 1 and OTC enzyme expression and activities, which may act as pacemaker of this ammonia detoxification pathway. Moreover, high ureagenesis in younger mice was accompanied by elevated periportal expression of hepatic glutamine synthetase, another main enzyme required for ammonia detoxification. These observations led us to perform a more extensive analysis of the spf(ash) mouse in comparison to the wild-type, including characterization of the corresponding metabolites, enzyme activities in the liver and plasma and the gut microbiota. In conclusion, the comprehensive enzymatic and metabolic analysis of ureagenesis performed in the presented depth was only possible in animals. Our findings suggest such analyses being essential when using the mouse as a model and revealed age-dependent activity of ammonia detoxification.

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