Dietary Arginine Requirements for Growth Are Dependent on the Rate of Citrulline Production in Mice

Marini, Juan C.; Agarwal, Umang; Didelija, Inka Cajo

doi:10.3945/jn.114.209668

Cited by 13 publications

(11 citation statements)

References 25 publications

(19 reference statements)

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“…Citrulline fluxes in 3 The contribution of glutamine to citrulline synthesis differed (P , 0.001) depending on the tracer and fragment used to determine isotope enrichment. mice were in the range of previous determinations for the same mouse strain (31) and in pigs were similar to previous determinations in animals of the same age (32). To the best of our knowledge, the citrulline fluxes reported here represent the first determination in rats with the use of stable isotopes.…”

Section: Discussionsupporting

confidence: 88%

Plasma Glutamine Is a Minor Precursor for the Synthesis of Citrulline: A Multispecies Study

Marini

Agarwal

Didelija

et al. 2017

The Journal of Nutrition

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Glutamine is considered the main precursor for citrulline synthesis in many species, including humans. The transfer of N from 2-[N]-glutamine to citrulline has been used as evidence for this precursor-product relation. However, work in mice has shown that nitrogen and carbon tracers follow different moieties of glutamine and that glutamine contribution to the synthesis of citrulline is minor. It is unclear whether this small contribution of glutamine is also true in other species. The objective of the present work was to determine the contribution of glutamine to citrulline production by using nitrogen and carbon skeleton tracers in multiple species. Humans ( = 4), pigs ( = 5), rats ( = 6), and mice ( = 5) were infused with l-2-[N]- and l-[H]-glutamine and l-5,5-[H]-citrulline. The contribution of glutamine to citrulline synthesis was calculated by using different ions and fragments: glutamine M+1 to citrulline M+1, 2-[N]-glutamine to 2-[N]-citrulline, and [H]-glutamine to [H]-citrulline. Species-specific differences in glutamine and citrulline fluxes were found ( < 0.001), with rats having the largest fluxes, followed by mice, pigs, and humans (all < 0.05). The contribution of glutamine to citrulline as estimated by using glutamine M+1 to citrulline M+1 ranged from 88% in humans to 46% in pigs. However, the use of 2-[N]-glutamine and 2-[N]-citrulline as precursor and product yielded values of 48% in humans and 28% in pigs. Furthermore, the use of [H]-glutamine to [H]-citrulline yielded lower values ( < 0.001), resulting in a contribution of glutamine to the synthesis of citrulline of ∼10% in humans and 3% in pigs. The recycling of the [N]-glutamine label overestimates the contribution of glutamine to citrulline synthesis compared with a tracer that follows the carbon skeleton of glutamine. Glutamine is a minor precursor for the synthesis of citrulline in humans, pigs, rats, and mice.

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Section: Discussionsupporting

confidence: 88%

Plasma Glutamine Is a Minor Precursor for the Synthesis of Citrulline: A Multispecies Study

Marini

Agarwal

Didelija

et al. 2017

The Journal of Nutrition

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“…In an attempt to generate significant differential ASL expression in adult enterocytes of Villin Cre :Asl f/f mice and control littermates, mice were maintained on an arginine-free diet. As previously described, the weight of these mice was 20% lower than that of the respective genotypes fed an arginine-sufficient diet ( Marini et al., 2015 ). Importantly, dietary arginine restriction resulted in expression of ASL in the intestines of control mice but not in the Villin Cre :Asl f/f animals, although no differences in the animal growth curves or immune infiltrates to the intestine were observed between CKO mice and controls ( Figure S1 G).…”

Section: Resultssupporting

confidence: 62%

Induction of Nitric-Oxide Metabolism in Enterocytes Alleviates Colitis and Inflammation-Associated Colon Cancer

et al. 2018

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SummaryNitric oxide (NO) plays an established role in numerous physiological and pathological processes, but the specific cellular sources of NO in disease pathogenesis remain unclear, preventing the implementation of NO-related therapy. Argininosuccinate lyase (ASL) is the only enzyme able to produce arginine, the substrate for NO generation by nitric oxide synthase (NOS) isoforms. Here, we generated cell-specific conditional ASL knockout mice in combination with genetic and chemical colitis models. We demonstrate that NO derived from enterocytes alleviates colitis by decreasing macrophage infiltration and tissue damage, whereas immune cell-derived NO is associated with macrophage activation, resulting in increased severity of inflammation. We find that induction of endogenous NO production by enterocytes with supplements that upregulate ASL expression and complement its substrates results in improved epithelial integrity and alleviation of colitis and of inflammation-associated colon cancer.

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“…As a consequence, plasma citrulline concentrations and fluxes were greater in these mice. The flux of arginine in the control mice was similar to previous reports in C57BL/6 mice (27). Because there was no circulating arginine, it was not possible to determine arginine fluxes in the ADI-PEG20-treated mice.…”

Section: Discussionsupporting

confidence: 82%

“…Arginine is considered conditionally indispensable because under certain physiologic [e.g., growth (27)] or pathophysiologic [e.g., endotoxemia, sepsis (28)] conditions the endogenous synthesis is insufficient to meet the increased demand for this amino acid. The endogenous synthesis of arginine relies on the production of citrulline by the small intestine, which is then utilized by the kidney (where ASS1 and ASL are highly expressed) to produce arginine (29).…”

Section: Discussionmentioning

confidence: 99%

The Citrulline Recycling Pathway Sustains Cardiovascular Function in Arginine-Depleted Healthy Mice, but Cannot Sustain Nitric Oxide Production during Endotoxin Challenge

Yuan

Mohammad

Betancourt³

et al. 2018

The Journal of Nutrition

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Background The recycling of citrulline by argininosuccinate synthase 1 (ASS1) and argininosuccinate lyase (ASL) is crucial to maintain arginine availability and nitric oxide (NO) production. Pegylated arginine deiminase (ADI-PEG20) is a bacterial enzyme used to deplete circulating arginine. Objective The goal of this research was to test the hypothesis that citrulline is able to sustain intracellular arginine availability for NO production in ADI-PEG20 arginine–depleted mice. Methods Six- to 8-wk-old male C57BL/6J mice injected with ADI-PEG20 (5 IU) or saline (control) were used in 4 different studies. Arginine, citrulline, and NO kinetics were determined by using stable isotopes in unchallenged (study 1) and endotoxin-challenged (study 2) mice. Blood pressure was determined by telemetry for 6 d after ADI-PEG20 administration (study 3), and vasomotor activity and ASS1 and ASL gene expression were determined in mesenteric arteries collected from additional mice (study 4). Results ADI-PEG20 administration resulted in arginine depletion (<1 compared with 111 ± 37 µmol/L) but in greater plasma citrulline concentrations (900 ± 123 compared with 76 ± 8 µmol/L; P < 0.001) and fluxes (402 ± 17 compared with 126 ± 4 µmol ⋅ kg−1 ⋅ h−1; P < 0.001) compared with controls. Endotoxin-challenged ADI-PEG20–treated mice produced less NO than controls (13 ± 1 compared with 27 ± 2 µmol ⋅ kg−1 ⋅ h−1; P < 0.001). No differences (P > 0.50) were observed for cardiovascular variables (heart rate, blood pressure) between ADI-PEG20–treated and control mice. Furthermore, no ex vivo vasomotor differences were observed between the 2 treatments. ADI-PEG20 administration resulted in greater gene expression of ASS1 (∼3-fold) but lower expression of ASL (–30%). Conclusion ADI-PEG20 successfully depleted circulating arginine without any effect on cardiovascular endpoints in healthy mice but limited NO production after endotoxin challenge. Therefore, the citrulline recycling pathway can sustain local arginine availability independently from circulating arginine, satisfying the demand of arginine for endothelial NO production; however, it is unable to do so when a high demand for arginine is elicited by endotoxin.

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Dietary Arginine Requirements for Growth Are Dependent on the Rate of Citrulline Production in Mice

Abstract: Background: In many species, including humans, arginine is considered a semiessential amino acid because under

Cited by 13 publications

References 25 publications

Plasma Glutamine Is a Minor Precursor for the Synthesis of Citrulline: A Multispecies Study

Plasma Glutamine Is a Minor Precursor for the Synthesis of Citrulline: A Multispecies Study

Induction of Nitric-Oxide Metabolism in Enterocytes Alleviates Colitis and Inflammation-Associated Colon Cancer

The Citrulline Recycling Pathway Sustains Cardiovascular Function in Arginine-Depleted Healthy Mice, but Cannot Sustain Nitric Oxide Production during Endotoxin Challenge

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