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Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616
Dear Editor:
The recent article by Russell et al. (1
) used respiration calorimetry in conjunction with nitrogen balance to measure protein oxidation of cats. These authors reported that cats readily oxidized the additional protein ingested when the diet was changed from one containing 35% of its energy as protein, to one containing 52% of the energy as protein. They concluded that these results do not support the suggestion that the lack of adaptation of the nitrogen catabolic enzymes (e.g., urea cycle enzymes, aspartic aminotransferase, alanine aminotransferase) is the basic reason for the high protein requirement of cats for maintenance (2
).
The authors’ observations are in agreement with other reports (3
) that cats are able to metabolize the protein in diets that are more than twice that required to maintain nitrogen balance as suggested by NRC (4
). We do not agree with the author’s suggestion that their results imply, in any way, that the reason for the high protein requirement of the cat is not the lack of down-regulation of the nitrogen catabolic enzymes. All data to date point to the inability of cats to down-regulate as the basis for the high protein requirement for maintenance. These authors examined only the effect of a normal to high protein levels in the diet, not normal to a low level of protein, which is required to address the question that they proposed.
In all omnivores and herbivores examined, the nitrogen catabolic enzymes and those involved in the first step in the catabolism of the essential amino acids are up and downregulated in response to an increase or decrease in dietary protein. However, in cats the nitrogen catabolic enzymes have consistently been found not to respond to changes in dietary protein (2
,5
). Also, the enzymes involved in the first step of the catabolism of the essential amino acids in cats exhibit only small changes in activities (3
,6
,7
), considerably less than reported in rats (8
–11
). In cats there is limited up- and downregulation of the activity of the enzymes involved in the first step of the catabolism of the essential amino acids, contributing to the efficient use of the essential amino acids. However, there is little or no up- or down-regulation of nitrogen catabolic enzymes such as occurs in rats (12
). This results in the inability of cats to conserve nitrogen and is responsible for the high requirement for dietary protein. The inability of cats to conserve nitrogen is reflected in the high obligatory endogenous urinary nitrogen of adult cats (13
) of 360 mg · kg body weight0.75 · day-1 which is much greater than that for humans, marmosets, rats, dogs and domestic pigs (62, 110, 128, 210, and 163 mg/kg body0.75 per day, respectively). Cats also have a much higher urinary nitrogen loss during long-term fasting than other mammals (14
) and kittens give very low PER and NPU values compared with rats given the same proteins (15
).
Nonmammalian carnivorous species that have a high protein requirement also appear to regulate their nitrogen catabolic enzymes similarly to cats. A number of nitrogen catabolic enzymes in rainbow trout do not respond to the protein:energy level in the diet (16
). Similar lack of adaptation has been reported in carnivorous birds including vultures (17
) and barn owls (18
).
The basis for the difference between cats and other noncarnivorous mammals can be better understood in the context of all the mechanisms the animal has to both conserve nitrogen when fed a low-protein diet, and to oxidize the surplus when presented with an immediate excess. The regulation of nitrogen loss in mammals is linked primarily with the control of the activities of the urea cycle enzymes, which occurs at four levels:
The first level is substrate regulation, when the concentration of ammonia and/or aspartate decreases or increases, there is a (large potential) decrease or increase of flow of nitrogen into the urea cycle with the subsequent increase or decrease in synthesis of urea. Most catabolic enzymes of nitrogen metabolism are working well below their Kms.
The second level, is allosteric regulation, N-acetyl glutamate (NAG) is an absolute allosteric activator for carbamoyl phosphate synthase, the first step in the synthesis of urea. Thus changes in the liver mitochondrial concentration of NAG will dictate changes in the activity of carbamoyl phosphate synthase and the synthesis of urea on a second by second basis. The concentration of NAG is affected by the activity of NAG synthase. The flux through NAG synthase is modulated by the concentration of glutamic acid (acetyl coenzyme A is always rather high in the liver mitochondria) and the allosteric activation of the enzyme by arginine. Both glutamate and arginine increase rapidly when there is an increase in protein intake. When the concentration of substrates decrease, NAG decreases as it diffuses out of the mitochondria and is cleaved by an acetylase.
The third level of control of the urea cycle occurs as the liver concentration of ornithine increases and decreases. During the postabsorptive state, or when feeding a low-protein-diet, ornithine is depleted by the relatively high activity of ornithine-delta-aminotransaminase in the liver, which limits the availability of ornithine for the acceptance of carbamyl phosphate to form citrulline. Thus the low concentration of ornithine in the liver markedly reduces the synthesis of urea during periods of low arginine, (during the postabsorptive state or during periods of low-protein intake).
The fourth level of regulation (if the first three are not adequate) is the up- and down-regulation of the enzymes involved in urea synthesis, including alanine and aspartic aminotransferases. These changes usually require increases or decreases in mRNA, but also increases and decreases in translation of the existing message or increases or decreases in the rates of degradation of the enzymes. The activities of these enzymes per unit weight of liver in omnivores and herbivores increase and decrease over a period of 1 to 5 d as the protein intake increases or decreases (19
,20
). Coupled with these changes there is an increase in weight of the liver in young, but minimal changes in older rats (12
). There is little or no change in the activities of these enzymes in the liver of cats with increasing or decreasing protein intake (2
,5
), but the size of the liver of cats increases markedly with high protein intakes making more total enzyme available (3
).
In rats adapted to a high-protein diet the concentration of total amino acids in plasma is similar to rats consuming a normal- or low-protein diet (21
). In contrast, in cats the concentrations of these amino acids are elevated (5
) and this alone increases the availability of amino acids for degradation.
In summary, the first three levels of regulation are all functioning in the cat (22
,23
) although the Ka of NAG synthase for arginine is five times higher in cats than in rats (23
). It appears that in cats the nitrogen catabolic enzymes per g liver are set at a constitutively high level, sufficient to enable the first three levels of control to effectively and efficiently oxidize any excess intake of dietary protein. The cost of this enzymatic pattern is a limited ability to conserve nitrogen at low nitrogen intakes, because of the inability to down-regulate the nitrogen catabolic enzymes to take the final step in nitrogen conservation. This appears to be beneficial to the cat, a strict carnivore, in that it has the ability to maintain blood glucose during fasting, and is always ready to handle a high protein intake from a postabsorptive state, just as Russell et al. (1
) have shown.
Manuscript received 13 May 2002. Revision accepted 5 June 2002.
LITERATURE CITED
1. Russell, K., Murgatroyd, R. R. & Batt, R. M. (2002) Net protein oxidation is adapted to dietary protein intake in domestic cats (Felis silvestris catus). J. Nutr. 132:456-460.
2. Rogers, Q. R., Morris, J. G. & Freedland, R. A. (1977) Lack of hepatic enzymatic adaptation to low and high levels of dietary protein in the adult cat. Enzyme 22:348-356.[Medline]
3. Park, T., Rogers, Q. R. & Morris, J. G. (1999) High dietary protein and taurine increase cysteine desulfhydration in kittens. J. Nutr. 129:2225-2230.
4. National Research Council (1986) Nutrient Requirements of Cats Revised edition 1986 National Academy Press Washington, DC. .
5. Tews, J. K., Rogers, Q. R., Morris, J. G. & Harper, A. E. (1984) Effect of dietary protein and GABA on food intake, growth and tissue amino acids in cats. Physiol. Behav. 32:301-308.[Medline]
6. Fau, D., Morris, J. G. & Rogers, Q. R. (1987) Effects of high dietary methionine on activities of selected enzymes in the liver of kittens. (Felis domesticus). Comp. Biochem. Physiol. 88B:551-555.
7. Bai, S. C., Rogers, Q. R., Wong, D. L., Sampson, D. A. & Morris, J. G. (1998) Vitamin B-6 deficiency and level of dietary protein affect hepatic tyrosine aminotransferase activity in cats. J. Nutr. 128:1995-2000.
8. Schimke, R. T., Sweeney, E. W. & Berlin, C. M. (1964) The role of synthesis and degradation in the control of rat liver tryptophan pyrrolase. J. Biol. Chem. 240:322-331.
9. Kaplan, J. H. & Pitot, H. C. (1970) The regulation of intermediary amino acid metabolism in animal tissue. Munro, H. N. eds. Mammalian Protein Metabolism 4:387-443 Academic Press New York, NY. .
10. Chu, S. H. & Hegsted, D. M. (1976) Adaptive response of lysine and threonine degrading enzymes in adult rats. J. Nutr. 106:1089-1096.
11. Kang-Lee, Y. A. & Harper, A. E. (1978) Threonine metabolism in vivo: effect of threonine intake and prior induction of threonine dehydratase in rats. J. Nutr. 108:163-175.
12. Schimke, R. T. (1962) Adaptive characteristics of urea cycle enzymes in the rat. J. Biol. Chem. 237:459-468.
13. Hendriks, W. H., Moughan, P. J. & Tarttelin, M. F. (1997) Urinary excretion of endogenous nitrogen metabolites in adult domestic cats using a protein-free diet and the regression technique. J. Nutr. 127:623-629.
14. Biourge, V., Groff, J. M., Fisher, C., Bee, D., Morris, J. G. & Rogers, Q. R. (1994) Nitrogen balance, plasma free amino acid concentrations and urinary orotic acid excretion during long term fasting in cats. J. Nutr. 124:1094-1103.
15. Fox, L.A.D., Jansen, G. R. & Knox, K. L. (1973) Effects of variations in protein quality on growth, PER, NPR and NPU in growing kittens. Nutr. Rep. Int. 7:621-631.
16. Cowey, C. B., Cooke, D. J., Matty, A. J. & Adron, J. W. (1981) Effects of quantity and quality of dietary protein on certain enzyme activities in rainbow trout. J. Nutr. 111:336-345.
17. Migliorini, R. H., Lindner, C., Moura, J. L. & Veiga, J. A. (1973) Gluconeogenesis in a carnivorous bird (black vulture). Am. J. Physiol. 225:1389-1392.
18. Myers, M. R. & Klasing, K. C. (1999) Low glucokinase activity and high rates of gluconeogenesis contribute to hyperglycemia in barn owls (Tyto alba) after a glucose challenge. J. Nutr. 129:1896-1904.
19. Das, T. K. & Waterlow, J. C. (1974) The rate of adaptation of urea cycle enzymes, aminotransferases, and glutamic dehydrogenase to changes in dietary protein intake. Br. J. Nutr. 32:353-373.[Medline]
20. Schimke, R. T. (1964) The importance of both synthesis and degradation in the control of arginase levels in rat liver. J. Biol. Chem. 239:3808-3817.
21. Anderson, H. L., Benevenga, N. J. & Harper, A. E. (1968) Associations among food and protein intake, serine dehydratase, and plasma amino acids. Am. J. Physiol. 214:1008-1013.
22. Morris, J. G. & Rogers, Q. R. (1978) Arginine: an essential amino acid for the cat. J. Nutr. 108:1944-1953.
23. Stewart, P. M., Batshaw, M., Valle, D. & Walser, M. (1981) Effects of arginine-free meals on ureagenesis in cats. Am. J. Physiol. 241:E310-E315.
This article has been cited by other articles:
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  A. S. Green, J. J. Ramsey, C. Villaverde, D. K. Asami, A. Wei, and A. J. Fascetti Cats Are Able to Adapt Protein Oxidation to Protein Intake Provided Their Requirement for Dietary Protein Is Met J. Nutr., June 1, 2008; 138(6): 1053 - 1060. [Abstract] [Full Text] [PDF]
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