The 2009 ESPEN Sir David Cuthbertson. Citrulline: a new major signaling molecule or just another player in the pharmaconutrition game?

Citrulline (CIT) is synthesized from arginine (ARG) and glutamine in enterocytes and metabolized by the kidneys into arginine, which is available for peripheral tissues. Thus CIT, rather than ARG, could be a limiting amino acid (AA) in situations of intestinal failure. This was verified in a rat model of short bowel syndrome. The effects of CIT were further tested in renutrition of malnourished rats and in healthy volunteers fed a hypoproteic diet. CIT supplementation improved protein synthesis (PS) and ARG availability more than ARG itself, which is explained by the fact that CIT, unlike ARG, is very efficiently transported into enterocytes and escapes hepatic uptake. Action of CIT on PS is mediated through the mTOR pathway. A key issue is why CIT should stimulate PS. CIT could be a counterpart of leucine, with leucine stimulating PS in the postprandial state, while CIT acts when protein intake is low or nil to maintain PS at a minimal level compatible with life. CIT could also be a safe way to deliver ARG to endothelial and immune cells, and can certainly prevent excessive uncontrolled nitric oxide production.