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4 Laboratoire de Biologie de la Nutrition, EA 2498, Faculté de Pharmacie, Université Paris Descartes, France and 5 Laboratoire Biochimie, Hôtel-Dieu, AP-HP, Paris 75004, France
* To whom correspondence should be addressed. E-mail: christophe.moinard{at}univ-paris5.fr.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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-amino group. Hence, the -carbon of CIT is oxidatively converted into aldehyde after releasing the amino and carboxyl groups of CIT (2). The high second-order rate constant for the reaction between CIT and hydroxyl radicals (3.9 x 109 M–1 s–1) (3) effectively protects DNA and metabolic enzymes from oxidative injuries.
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The interorgan metabolism of CIT
CIT displays a unique metabolism. Briefly, after arginine (ARG) or glutamine (GLN) intake, the small intestine releases large amounts of CIT (4,5). Pioneering studies with Windmuller and Spaeth (4) showed that CIT is an end product of intestinal GLN metabolism, and it accounts for 27.6% of the metabolized GLN nitrogen. Moreover, CIT can also be synthesized in the intestine from ARG because the enterocytes possess the 2 enzymes (arginase II and ornithine carbamoyl transferase) needed for CIT synthesis. However, the activity of the 2 enzymes that catabolize CIT [argininosuccinate synthase (ASS) and argininosuccinate lyase (ASL)] is very low in the intestine (6,7). Therefore, CIT cannot be used in situ, and it is released as such into the circulation. It is of major importance to note that CIT is not taken up by the liver but is mainly taken up by the kidney. Because the kidney possesses ASS and ASL activities but not the other enzymes of the urea cycle, ARG is released, and 
75% of CIT produced by the gut is taken up by the kidney (8) (Fig. 2). It is important to note that the intestinal synthesis rate of CIT is the crucial regulatory event in the renal ARG synthesis (9). This ARG-CIT-ARG interorgan cycle can be seen as a means to protect dietary ARG from excessive liver degradation [because most dietary ARG is catabolized by liver arginase (10)] and to correctly adapt the ureagenesis rate according to protein intake because ARG is a major positive ureagenesis regulator [ARG is the activator of N-acetylglutamate, which in turn activates carbamoylphosphate synthase (11)]. GLN is the second major substrate regulating the ureagenesis rate because ammonia derived from GLN metabolism up-regulates liver glutaminase (12). Thus, CIT can be seen as a means to sustain protein homeostasis, especially in situations where the intake of protein is low (7). In these situations, OCT expression in the intestine increases, thus promoting the formation of CIT and thereby allowing the down-regulation of liver ureagenesis (13).
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-N-(phosphonacetyl)-L-ornithine (PALO), which selectively inhibits OCT. When PALO was administered in drinking water to 6-wk-old rat pups fed an arginine-deficient diet, plasma concentrations of CIT and ARG were reduced, and this caused a rapid and complete inhibition of growth in rats fed ARG-deficient diets. Moreover, prolonged administration of PALO (i.e., >10 d) was associated with an increase in mortality. Interestingly, mortality and growth inhibition were partially prevented by simultaneous administration of 1% (wt:wt) ARG to the diet (although this did not allow catch-up growth) and were completely prevented with 1% (wt:wt) CIT supplementation. Thus, this work clearly shows the importance of intestinal CIT synthesis for the preservation of nitrogen homeostasis. Citrulline: a marker of renal failure
As discussed above, kidneys are the main organs that metabolize CIT because ASS and ASL are expressed along their tubules (15,16). As a consequence, renal failure is associated with an impairment of CIT metabolism. In an attempt to establish the correlation between citrullinemia and renal insufficiency, Levillain et al. (17) performed an experimental study in which rats were subjected to degrees of nephrectomy (NX) varying between 10% and 90%. Three weeks later, plasma CIT concentration was increased compared with sham-operated rats and was correlated with the degree of NX. More interestingly, plasma CIT was increased in mild renal failure (i.e., in the range of 10 to 33% NX) without any changes in uremia and creatininemia, 2 well-known markers of uremic states. A second experimental series was designed to study the time course of changes in aminoacidemia to find a marker for the onset of renal failure. Rats were subjected to 36% NX for a period of 1 to 21 d. Uremia and creatininemia peaked 24 to 48 h after NX, and creatinine clearance concomitantly decreased. However, these 3 markers of uremic states returned to control values during the next few days before increasing during the last 2 wk. In contrast, plasma CIT concentration increased 2-fold 48 h after NX and remained at a high level over the next 20 d. It appeared that CIT could be used 1) to detect acute and chronic renal failure, 2) as a specific marker of normal function for the proximal tubules, and 3) to estimate the degree of renal damage. In humans, plasma CIT concentration is increased according to the progression of renal failure, and there is a good correlation between CIT and the plasma concentration of creatinine (18).
Citrulline: a marker of intestinal failure
Physiologically, the plasma concentration of CIT reflects the difference between the intestinal production and its metabolism into ARG by the kidney (19). It is noteworthy that the small intestine is the only significant source of circulating CIT, and this raised the hypothesis of a possible relation between intestinal mass and plasma CIT concentration provided the renal function is normal (see above). For this reason CIT was proposed as a potentially good marker of functional intestinal mass. This concept was first validated by Crenn et al. (20) in short bowel syndrome (SBS) patients where postabsorptive plasma CIT appears to be a valuable biomarker in the diagnosis and outcome of intestinal failure. In this pioneering work, postabsorptive CIT concentration was measured in 57 patients, with a minimal follow-up of 2 y, and the definitions of permanent (n = 37) and transient (n = 20) intestinal failure were based on parenteral nutrition dependence. The results clearly showed that plasma CIT was correlated to small bowel length and to net digestive absorption of fat. A cutoff at 20 µmol/L was established to classify short bowel patients with permanent intestinal failure with high sensitivity (92%), specificity (90%), and positive predictive value (95%). The conclusion of this work is that CIT is a marker of functional absorptive bowel length and, past the 2-y adaptive period, a powerful independent indicator that makes it possible to distinguish between transient and permanent intestinal failure. The recent study of Jianfeng et al. (21) has confirmed the validity of CIT as a marker of small intestinal enterocyte mass and absorption function in SBS patients. Serum CIT levels in SBS patients correlated well with the remnant small bowel length, surface area, and intestinal absorption (evaluated by urine D-xylose excretion) and digestive protein absorption.
Finally, in another recent work, Rhoads et al. (22) found that serum CIT level in SBS infants correlated linearly with bowel length and tolerance to calorie intake. They concluded that serum CIT level >19 µmol/L in children with SBS is associated with the development of enteral tolerance and may be a useful predictive test for that purpose. These results are in accord with preliminary results obtained by Wasa et al. (23).
This concept was then extended to other pathologies leading to intestinal failure. First, Crenn et al. (24) established that CIT is a marker of the extent and severity of villous atrophy in patients with celiac disease. They clearly showed that plasma CIT concentration was lower in patients with villous atrophy than in healthy subjects (24 ± 13 vs. 40 ± 10 µmol/L, P < 0.01) and that CIT was correlated to the severity and extent of villous atrophy (r = 0.81; P < 0.001). They also proposed a stratification that allows one to associate citrullinemia and intestinal disease: <10 µmol/L for patients with diffuse total villous atrophy; 10–20 µmol/L for patients with proximal-only total villous atrophy; 20–30 µmol/L for patients with partial villous atrophy. This work concluded that, in patients with villous atrophy diseases, plasma CIT concentration was correlated to the extent and severity of villous atrophy and may be a simple and reliable marker of reduced enterocyte mass.
In the same way, Lutgens et al. (25) suggested that CIT could be used for quantifying radiation-induced epithelial cell loss. Hence, small bowel irradiation results in epithelial cell loss and consequently impairs intestinal functions and metabolism. Using a model of irradiated mice, they showed that citrullinemia was correlated with morphologic parameters (CIT was correlated with jejunal crypt regeneration and epithelial surface lining). The same authors confirmed that plasma CIT concentration was correlated to epithelial cell loss, a major event in acute radiation-induced small-bowel toxicity in patients treated with fractionated radiation therapy for abdominal or pelvic cancer sites (26). In patients with hematologic malignancies who were receiving myeloablative therapy, serum CIT concentration was negatively correlated with sugar permeability tests (27).
Finally, serum CIT level may be a marker for acute cellular rejection in small intestinal transplant recipients (28,29). These authors observed that decreasing or slowly increasing CIT levels correlate with higher grades of rejection after 14 d posttransplant: the patients achieving CIT levels >30 µmol/L in <90 d correlate with lower grades of acute cellular rejection after this period. The same group (30) has proposed the utilization of dried blood spot (DBS) applied to CIT determination as a method for monitoring graft function following intestinal transplantation. The DBS method is a less invasive and more convenient way to obtain blood samples than venipuncture, especially when small amounts of blood are required from infants and children or to follow up patients when they go home. A linear correlation was observed between HPLC-based and DBS-based CIT concentration determinations. However, the large dispersion of values obtained using DBS precludes any useful application in clinical practice for the moment.
Citrulline: a new nutritional therapeutic
On the whole, all the situations characterized by an impairment of the active intestinal mass lead to a hypocitrullinemia proportional to the severity of the disease. As a consequence, decreasing levels of ARG are also observed (31). Because low CIT production means low de novo ARG synthesis, it would make sense to provide extra ARG to patients with intestinal failure (32). But, as mentioned above, ARG is taken up by the liver, and its supplementation may potentially be unsafe in certain situations because of its role as nitric oxide precursor. Conversely, providing CIT is an elegant way to fill in ARG pools. Thus, it was hypothesized that CIT, rather than ARG, should be administered when the intestinal function is compromised. In this way, using a model of resected rats, we recently demonstrated (33) that supplementation of continuous enteral nutrition with CIT increases ARG pools and restores nitrogen balance after massive intestinal resection (80%) in rats. In addition, CIT was more effective than an isomolar ARG supplementation. As expected, CIT content in the liver did not vary in response to CIT supplementation, whereas there was a large accumulation of CIT in all the other tissues. This work is a good illustration that, unlike ARG, which is extensively taken up by the liver and extensively metabolized into urea, CIT passes freely through the liver.
When CIT was given parenterally in addition to a standard formula in the same model of SBS, similar results were obtained, but, interestingly, ARG supplementation was clearly deleterious in terms of nitrogen balance (34). Moreover, in this work, CIT had a positive effect on the intestinal adaptation in terms of intestinal mucosa weight and protein content, and CIT was also able to limit the body weight loss associated with SBS (34).
The ability of CIT to improve nitrogen homeostasis was also observed in a model of renutrition of protein-energy malnutrition in aged rats. There is a strong rationale to study the effects of CIT supplementation in this situation. First, although the intestinal function is well preserved with aging, gut atrophy is commonly observed in malnourished elderly people (35). Second, malnourished elderly people (36) and old rats (37) are resistant to renutrition; and third, there is a significant increase in AA metabolism within the splanchnic area in the elderly compared with adults (38–41). This high splanchnic extraction of AA in the elderly leads to inadequate systemic plasma levels of AA in the postprandial period (42). Based on these data, we postulated that by administering an AA that escapes splanchnic extraction, namely CIT, it would be possible to deliver a more adequate amount of nitrogen to peripheral tissues. To verify this concept, we used a well-validated model of old malnourished rats in which an impaired response to renutrition had been proven (37,43). Interestingly, our results clearly showed that CIT supplementation during refeeding of old malnourished rats increases muscle protein content (+20%, P < 0.05) by stimulating protein synthesis (+90%, P < 0.05).
In conclusion, supplementation of the diet with CIT in 2 very different situations leads to a dramatic improvement of nitrogen balance and protein status. The question that is now raised is how can CIT stimulate muscle protein synthesis? The latter could be 1) indirect, i.e., related to its ability to generate ARG or to stimulate insulin and growth hormone secretion, or CIT may simply be a vehicle bringing nitrogen to the muscle, or 2) direct; to date, the transductional properties of CIT are not known. However, recent preliminary data incubating isolated muscle with CIT suggest that CIT could be able to directly stimulate protein synthesis (44). Hence, it appears that CIT could play a key role in protein homeostasis, and the determination of the underlying mechanisms involved in its action should be important not only for the development of new nutritional strategies but also physiologically, as discussed hereafter.
The role of citrulline in control of protein metabolism: a new working hypothesis
Examining the effects of CIT on protein metabolism raises several questions. Why is the interorgan metabolism of CIT so sophistically regulated? Why does this nonprotein AA have an effect on muscle protein synthesis?
To explain this result, we propose a new working hypothesis: To our knowledge, only 1 AA, namely leucine (LEU), was proven to have a direct effect on muscle protein synthesis (45,46). However, to exert this action, availability of other essential AAs together with high insulinemia is necessary, which corresponds to the postprandial situation (47). Conversely, CIT is synthesized and released by the intestine mainly in the situation of low protein intake or in the postabsorptive state (7). Our working hypothesis is that LEU and CIT would be the 2 essential AAs in controlling nitrogen balance and muscle protein composition, depending on the nutritional state.
At the postprandial state, the significant provision of LEU is a stimulus for insulin secretion, and, in the presence of other essential AAs, this elicits maximum muscle protein synthesis (Fig. 3 A). In contrast, in the postabsorptive state or in the situation of low protein intake, a minimal protein synthesis level has to be sustained to be compatible with life. In these situations, CIT availability would be increased and would be able to maintain basal insulin secretion (48) and minimal protein synthesis (Fig. 3 B).
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FOOTNOTES |
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2 Author disclosures: C. Moinard, The International Council on Amino Acid Science (ICAAS) paid travel expenses to the meeting; and L. Cynober, The International Council on Amino Acid Science (ICAAS) paid travel expenses to the meeting.
3 Supported by a grant from Laboratoires Biocodex and by the quadriennal programme (EA 2498) from the French Ministerium of Research and Technology.
6 Abbreviations used: AA, amino acid; ARG, arginine; ASL, argininosuccinate lyase; ASS, argininosuccinate synthase; CIT, citrulline; DBS, dried blood spot; GLN, glutamine; LEU, leucine; NX, nephrectomy; PALO, glycylglycine -N-(phosphonacetyl)-L-ornithine; SBS, short bowel syndrome.
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