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Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions

Ornithine Restores Ureagenesis Capacity and Mitigates Hyperammonemia in Otc^spf-ash Mice¹

Juan C. Marini^*,2,3, Brendan Lee and Peter J. Garlick^*

^* Animal Science Department, University of Illinois, Urbana IL 61801 and Molecular and Human Genetics and Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030

³ To whom correspondence should be addressed. Email: jcmarini{at}uiuc.edu.

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 ([¹³C¹⁸O]urea, [5-¹⁵N]glutamine, [2,3,3,4,4 D₅]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 ± 17µmol/(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.

KEY WORDS: • glutamine • spf-ash mouse • ornithine • OTCD • urea cycle disorders

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				J. C. Marini, A. Erez, L. Castillo, and B. Lee Interaction between murine spf-ash mutation and genetic background yields different metabolic phenotypes Am J Physiol Endocrinol Metab, December 1, 2007; 293(6): E1764 - E1771. [Abstract] [Full Text] [PDF]