Ornithine restores ureagenesis capacity and mitigates hyperammonemia in Otc^spf-ash mice

We showed that Otc^spf-ash mice, a model of ornithine transcarbamylase deficiency, were able to sustain ureagenesis at the same rate as control mice, despite reduced enzyme activity, when a complete mixture of amino acids was provided. An unbalanced amino acid mixture, however, resulted in reduced ureagenesis and hyperammonemia. To study the effect of ornithine supplementation [316 μmol/(kg·h)] on urea and glutamine kinetics in conscious Otc^spf-ash mice under a glycine-alanine load [6.06 mmol/(kg·h)], a multiple tracer infusion protocol ([¹³C ¹⁸O]urea, [5-¹⁵N]glutamine, [2,3,3,4,4 D ₅]glutamine and [ring-D₅] phenylalanine) was conducted. Ornithine supplementation increased ureagenesis [3.18 ± 0.88 vs. 4.56 ± 0.51 mmol/(kg·h), P < 0.001], reduced plasma ammonia concentration (1125 ± 621 vs. 193 ± 94 μmol/L, P < 0.001), and prevented acute hepatic enlargement (P < 0.006) in Otc^spf-ash mice. Ornithine supplementation also increased [96 ± 20 vs. 120 ± 16 μmol/(kg·h), P < 0.001] the transfer of ¹⁵N from glutamine to urea, to values observed in the control mice [123 ± 17 μmol/(kg·h)]. De novo amido-N glutamine flux was higher [1.57 ± 0.37 vs. 3.04 ± 0.86 mmol/(kg·h); P < 0.001] in Otc ^spf-ash mice, but ornithine supplementation had no effect (P < 0.56). The flux of glutamine carbon skeleton was affected by both genotype (P < 0.0001) and by ornithine (P 0. 036). In conclusion, ornithine supplementation restored ureagenesis, mitigated hyperammonemia, prevented liver enlargement, and normalized the transfer of ¹⁵N from glutamine to urea. These data strongly suggest that ornithine has the potential for the biochemical correction of OTCD in Otc^spf-ash mice.