高氨血症
鸟氨酸转氨酶
尿素循环
戒毒(替代医学)
乳清酸
鸟氨酸转氨酶缺乏症
酶
谷氨酰胺
生物化学
分解代谢
鸟氨酸
生物
新陈代谢
精氨酸
内科学
内分泌学
氨基酸
医学
病理
替代医学
作者
Gabriella Allegri,Sereina Deplazes,Nicole Rimann,Benjamin Causton,Tanja Scherer,Jonathan W. Leff,Carmen Dı́ez-Fernández,Anna Klimovskaia,Ralph Fingerhut,Jakub Krijt,Viktor Kožich,Jean‐Marc Nuoffer,Hiu Man Grisch‐Chan,Beat Thöny,Johannes Häberle
摘要
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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