Interaction between murinespf-ashmutation and genetic background yields different metabolic phenotypes

Abstract

The spf-ash mutation in mice results in reduced hepatic and intestinal ornithine transcarbamylase. However, a reduction in enzyme activity only translates in reduced ureagenesis and hyperammonemia when an unbalanced nitrogen load is imposed. Six-week-old wild-type control and spf-ash mutant male mice from different genetic backgrounds (B6 and ICR) were infused intravenously with [13C18O]urea, l-[15N2]arginine, l-[5,5 D2]ornithine, l-[6-13C, 4,4,5,5, D4]citrulline, and l-[ring-D5]phenylalanine to investigate the interaction between genetic background and spf-ash mutation on ureagenesis, arginine metabolism, and nitric oxide production. ICRspf-ashmice maintained ureagenesis (5.5 ± 0.3 mmol·kg−1·h−1) and developed mild hyperammonemia (145 ± 19 μmol/l) when an unbalanced nitrogen load was imposed; however, B6spf-ashmice became hyperammonemic (671 ± 15 μmol/l) due to compromised ureagenesis (3.4 ± 0.1 mmol·kg−1·h−1). Ornithine supplementation restored ureagenesis and mitigated hyperammonemia. A reduction in citrulline entry rate was observed due to the mutation in both genetic backgrounds (wild-type: 128, spf-ash: 60; SE 4.0 μmol·kg−1·h−1). Arginine entry rate was only reduced in B6spf-ashmice (B6spf-ash: 332, ICRspf-ash: 453; SE 20.6 μmol·kg−1·h−1). Genetic background and mutation had an effect on nitric oxide production (B6: 3.4, B6spf-ash: 2.8, ICR: 9.0, ICRspf-ash: 4.6, SE 0.7 μmol·kg−1·h−1). Protein breakdown was the main source of arginine during the postabsorptive state and was higher in ICRspf-ashthan in B6spf-ashmice (phenylalanine entry rate 479 and 327, respectively; SE 18 μmol·kg−1·h−1). Our results highlight the importance of the interaction between mutation and genetic background on ureagenesis, arginine metabolism, and nitric oxide production. These observations help explain the wide phenotypic variation of ornithine transcarbamylase deficiency in the human population.