The physiological basis and nutritional function of Alpha-ketoglutarate

Current Protein and Peptide Science

Volumn 16, Issue 7, 2015, Pages 576-581

  He, Liuqin ^a,b   Xu, Zhiqi ^c   Yao, Kang ^a   Wu, Guoao ^a,e,g   Yin, Yulong ^a   Nyachoti, Clares M ^d   Kim, Sung Woo ^e,f  

^a INSTITUTE OF GEOLOGY AND GEOPHYSICS   (China)

^b UNIVERSITY OF CHINESE ACADEMY OF SCIENCES   (China)

^c NANCHANG HANGKONG UNIVERSITY   (China)

^d UNIVERSITY OF MANITOBA   (Canada)

^e TEXAS A AND M UNIVERSITY   (United States)

^f NORTH CAROLINA STATE UNIVERSITY   (United States)

^g WUHAN POLYTECHNIC UNIVERSITY   (China)

Author keywords

Alpha Ketoglutarate; Glutamate; Glutamine; Nutrition; Physiological; Protein synthesis

Indexed keywords

2 OXOGLUTARIC ACID; ALPHA-KETOGLUTARIC ACID; ANTIOXIDANT;

ARTICLE; BONE METABOLISM; BONE MINERALIZATION; GASTROINTESTINAL TRACT; GENE EXPRESSION; HUMAN; IMMUNE FUNCTION TEST; INTESTINE MUCOSA; NONHUMAN; NUTRITIONAL ASSESSMENT; NUTRITIONAL HEALTH; OXIDATIVE STRESS; PARENTERAL NUTRITION; PHYSIOLOGICAL PROCESS; PROTEIN METABOLISM; PROTEIN SYNTHESIS; SIGNAL TRANSDUCTION; ANIMAL; ENERGY METABOLISM; IMMUNOLOGY; INTESTINE; METABOLISM; OXIDATION REDUCTION REACTION;

ANIMALIA; MAMMALIA;

ANIMALS; ANTIOXIDANTS; CALCIFICATION, PHYSIOLOGIC; ENERGY METABOLISM; HUMANS; INTESTINES; KETOGLUTARIC ACIDS; OXIDATION-REDUCTION;

EID: 84939779720     PISSN: 13892037     EISSN: 18755550     Source Type: Journal    
DOI: 10.2174/1389203716666150630140157     Document Type: Article

References (71)

1. Ninfa, A.J.; Jiang, P. PII signal transduction proteins: sensors of alpha-ketoglutarate that regulate nitrogen metabolism. Curr. Opin. Microbiol., 2005, 8, 168-173.
2. Teplan, V.; Schuck, O.; Votruba, M.; Poledne, R.; Kazdova, L.; Skibova, J.; Maly, J. Metabolic effects of keto acid - amino acid supplementation in patients with chronic renal insufficiency receiving a low-protein diet and recombinant human erythropoietin-A randomized controlled trial. Wien Klin Wochenschr, 2001, 113, 661-669.
3. Riedel, E.; Nundel, M.; Hampl, H. Alpha-Ketoglutarate application in hemodialysis patients improves amino acid metabolism. Nephron., 1996, 74, 261-265.
4. Riedel, E.; Hampl, H.; Steudle, V.; Nundel, M. Calcium alphaketoglutarate administration to malnourished hemodialysis patients improves plasma arginine concentrations. Miner. Electrol. Metab., 1996, 22, 119-122.
5. Coudray-Lucas, C.; Le Bever, H.; Cynober, L.; De Bandt, J.P.; Carsin, H. Ornithine alpha-ketoglutarate improves wound healing in severe burn patients: A prospective randomized double-blind trial versus isonitrogenous controls. Crit. Care. Med., 2000, 28, 1772-1776.
6. Ingraham, L.; Li, M.S.; Renfro, J.L.; Parker, S.; Vapurcuyan, A.; Hanna, I.; Pelis, R.M. A Plasma concentration of alphaketoglutarate influences the kinetic interaction of ligands with organic anion transporter 1. Mol. Pharmacol., 2014, 86, 86-95.
7. Moinard, C.; Dauge, V.; Cynober, L. Ornithine alpha-ketoglutarate supplementation influences motor activity in healthy rats. Clin. Nutr., 2004, 23, 485-490.
8. Schuster, H.; Blanc, M.C.; Genthon, C.; Therond, P.; Bonnefont- Rousselot, D.; Le Tourneau, A.; De Bandt, J.P.; Cynober, L. Does dietary ornithine alpha-ketoglutarate supplementation protect the liver against ischemia-reperfusion injury? Clin. Nutr., 2005, 24, 375-384.
9. Segaud, F.; Combaret, L.; Neveux, N.; Attaix, D.; Cynober, L.; Moinard, C. Effects of ornithine alpha-ketoglutarate on protein metabolism in Yoshida sarcoma-bearing rats. Clin. Nutr., 2007, 26, 624-630.
10. Wu, G. Amino Acids: Biochemistry and Nutrition. 2013. CRC Press, Boca Raton.
11. Filip, R.; Wdowiak, L.; Harrison, A.P.; Pierzynowski, S.G. Dietary supplementation with phytohemagglutinin in combination with alpha-ketoglutarate limits the excertion of nitrogen via urinary tract. Ann. Agr. Env. Med., 2008, 15, 309-315.
12. Welborn, J.R.; Shpun, S.; Dantzler, W.H.; Wright, S.H. Effect of alpha-ketoglutarate on organic anion transport in single rabbit renal proximal tubules. Am. J. Physiol. Renal. Physiol., 1998, 274, 165- 174.
13. Lambert, B.D.; Filip, R.; Stoll, B.; Junghans, P.; Derno, M.; Hennig, U.; Souffrant, W.B.; Pierzynowski, S.; Burrin, D.G. Firstpass metabolism limits the intestinal absorption of enteral alphaketoglutarate in young pigs. J. Nutr., 2006, 136, 2779-2784.
14. Wu, G.Y.; Bazer, F.W.; Davis, T.A.; Kim, S.W.; Li, P.; Rhoads, J.M.; Satterfield, M.C.; Smith, S.B.; Spencer, T.E.; Yin, Y.L. Arginine metabolism and nutrition in growth, health and disease. Amino Acids, 2009, 37, 153-168.
15. Ren, W.K.; Duan, J.L.; Yin, J.; Liu, G.; Cao, Z,; Xion, X.; Chen, S.; Li, T.J.; Yin, Y.L.; Hou, Y.Q.; Wu, G. Dietary L-glutamine supplementation modulates microbial community and activates innate immunity in the mouse intestine. Amino Acids, 2014, 46, 2403-2413.
16. LeBricon, T.; CoudrayLucas, C.; Lioret, N.; Lim, S.K.; Plassart, F.; Schlegel, L.; DeBandt, J.P.; Saizy, R.; Giboudeau, J.; Cynober, L. Ornithine alpha-ketoglutarate metabolism after enteral administration in burn patients: Bolus compared with continuous infusion. Am. J. Clin. Nutr., 1997, 65, 512-518.
17. Wu, G.; Bazer, F.W.; Johnson, G.A.; Knabe, D.A.; Burghardt, R.C.; Spencer, T.E.; Li, X.L.; Wang, J.J. Important roles for Lglutamine in swine nutrition and production. J. Anim. Sci., 2011, 89, 2017-2030.
18. Aussel, C.; CoudrayLucas, C.; Lasnier, E.; Cynober, L.; Ekindjian, O.G. Alpha-Ketoglutarate uptake in human fibroblasts. Cell. Biol. Int., 1996, 20, 359-363.
19. Schuster, H.; Blanc, M.C.; Bonnefont-Rousselot, D.; Nakib, S.; Le Tourneau, A.; Furst, P.; Cynober, L.; De Bandt, J.P. Protective effects of glutamine dipeptide and alpha-tocopherol against ischemia-reperfusion injury in the isolated rat liver. Clin. Nutr., 2009, 28, 331-337.
20. Haynes, T.E.; Li, P.; Li, X.L.; Shimotori, K.; Sato, H.; Flynn, N.E.; Wang, J.J.; Knabe, D.A.; Wu, G.Y. L-Glutamine or L-alanyl-lglutamine prevents oxidant-or endotoxin-induced death of neonatal enterocytes. Amino Acids, 2009, 37, 131-142.
21. Pierzynowski, S.G.; Sjodin, A. Perspectives of glutamine and its derivatives as feed additives for farm animals. J. Anim. Feed Sci., 1998, 7, 79-91.
22. Kristensen, N.B.; Jungvid, H.; Fernandez, J.A.; Pierzynowski, S.G. Absorption and metabolism of alpha-ketoglutarate in growing pigs. J. Anim. Physiol. Nutr., 2002, 86, 239-245.
23. Elango, R.; Ball, R.O.; Pencharz, P.B. Amino acid requirements in humans: with a special emphasis on the metabolic availability of amino acids. Amino Acids, 2009, 37, 19-27.
24. Matthews, D.E.; Marano, M.A.; Campbell, R.G. Splanchnic bed utilization of leucine and phenylalanine in humans. Am. J. Physiol., 1993, 264, 109-118.
25. Ali, R.; Mittal, G.; Sultana, S.; Bhatnagar, A. Ameliorative potential of alpha-ketoglutaric acid (AKG) on acute lung injuries induced by ammonia inhalation in rats. Exp. Lung Res., 2012, 38, 435-444.
26. Hammarqvist, F.; Wernerman, J.; Vonderdecken, A.; Vinnars, E. Alpha-ketoglutarate preserves protein-synthesis and free glutamine in skeletal-muscle after surgery. Surgery, 1991, 109, 28-36.
27. Le Boucher, J.; Obled, C.; Farges, M.C.; Cynober, L. Ornithine alpha-ketoglutarate modulates tissue protein metabolism in burninjured rats. Am. J. Physiol., 1997, 273, E557-563.
28. Wiren, M.; Permert, J.; Larsson, J. Alpha-ketoglutaratesupplemented enteral nutrition. Effects on postoperative nitrogen balance and muscle catabolism. Nutrition, 2002, 18, 725-728.
29. Dabek, M.; Kruszewska, D.; Filip, R.; Hotowy, A.; Pierzynowski, L.; Wojtasz-Pajak, A.; Szymanczyk, S.; Piedra, J.L.V.; Werpachowska, E.; Pierzynowski, S.G. alpha-ketoglutarate (AKG) absorption from pig intestine and plasma pharmacokinetics. J. Anim. Physiol. Nutr., 2005, 89, 419-426.
30. Junghans, P.; Derno, M.; Pierzynowski, S.; Hennig, U.; Souffrant, W.B. Utilization of alpha-ketoglutarate (AKG) in young growing pigs after intra-venous and intra-duodenal administration. EAAP Publication, 2003, 109, 521-523.
31. Kowalik, S.; Filip, R.S.; Sliwa, E.; Tatara, M.R.; Pierzynowski, S.G.; Studzinski, T. Influence of alpha-ketoglutarate on bone mineral density of the femur in piglets. Bull. Vet. Inst. Pulawy., 2005, 49, 343-348.
32. Kowalik, S.; Sliwa, E.; Tatara, M.R.; Krupski, W.; Majcher, P.; Studzinski, T. Influence of alpha-ketoglutarate on mineral density and geometrical and mechanical parameters of femora during postnatal life in piglets. Bull. Vet. Inst. Pulawy., 2005, 49, 107-111.
33. Sliwa, E.; Kowalik, S.; Tatara, M.R.; Krupski, W.; Majcher, P.; Luszczewska-Sierakowska, I.; Pierzynowski, S.G.; Studzinski, T. Effect of alpha-ketoglutarate given to pregnant sows on the development of the humerus and femur in newborns. Bull. Vet. Inst. Pulawy., 2005, 49, 117-120.
34. Yao, K.; Yin, Y.; Li, X.; Xi, P.; Wang, J.; Lei, J.; Hou, Y.; Wu, G. Alpha-ketoglutarate inhibits glutamine degradation and enhances protein synthesis in intestinal porcine epithelial cells. Amino Acids, 2012, 42, 2491-2500.
35. Winkler, S.; Holzenbein, T.; Karner, J.; Roth, E. Kinetics of organ specific metabolism of a bolus injection into the jejunum of glutamine, alpha-ketoglutarate, ornithine and ornithine - alphaketoglutarate. Clin. Nutr., 1993, 12, 56-57.
36. Coudray-Lucas, C.; Lasnier, E.; Renaud, A.; Ziegler, F.; Settembre, P.; Cynober, L.A.; Ekindjian, O.G. Is alpha-ketoisocaproyl glutamine a suitable glutamine precursor to sustain fibroblast growth? Clin. Nutr., 1999, 18, 29-33.
37. Raul, F.; Gosse, F.; Galluser, M.; Hasselmann, M.; Seiler, N. Functional and Metabolic Changes in intestinal-mucosa of rats after enteral administration of ornithine alpha-ketoglutarate salt. Jpen- Parenter Enter., 1995, 19, 145-150.
38. Hou, Y.Q.; Wang, L.; Ding, B.Y.; Liu, Y.L.; Zhu, H.L.; Liu, J.; Li, Y.T.; Kang, P.; Yin, Y.L.; and Wu, G.Y. Alpha-Ketoglutarate and intestinal function. Front Biosci., 2011, 16, 1186-1196.
39. Fillmann, H.; Kretzmann, N.A.; San-Miguel, B.; Llesuy, S.; Marroni, N.; Gonzalez-Gallego, J.; Tunon, M.J. Glutamine inhibits over-expression of pro-inflammatory genes and down-regulates the nuclear factor kappaB pathway in an experimental model of colitis in the rat. Toxicology, 2007, 236, 217-226.
40. Hou, Y.Q.; Wang, L.; Ding, B.Y.; Liu, Y.L.; Zhu, H.L.; Liu, J.A.; Li, Y.T.; Wu, X.; Yin, Y.L.; Wu, G.Y. Dietary alpha-ketoglutarate supplementation ameliorates intestinal injury in lipopolysaccharide-challenged piglets. Amino Acids, 2010, 39, 555- 564.
41. Mullen, A.R.; Hu, Z.; Shi, X.; Jiang, L.; Boroughs, L.K.; Kovacs, Z.; Boriack, R.; Rakheja, D.; Sullivan, L.B.; Linehan, W.M.; et al. Oxidation of alpha-ketoglutarate is required for reductive carboxylation in cancer cells with mitochondrial defects. Cell Rep., 2014, 7, 1679-1690.
42. Liu, Y.F.; Lange, R.; Langanky, J.; Hamma, T.; Yang, B.Q.; Steinacker, J.M. Improved training tolerance by supplementation with alpha-Keto acids in untrained young adults: a randomized, double blind, placebo-controlled trial. J. Int. Soc. Sport Nutr., 2012, 9, 1550-2783.
43. Prandini, A.; Morlacchini, M.; Sigolo, S.; Fiorentini, L.; Gallo, A. Anticatabolic activity of alpha-ketoglutaric acid in growing rats. Ital. J. Anim. Sci., 2012, 11, 279-284.
44. Cynober, L.; Coudraylucas, C.; Debandt, J.P.; Guechot, J.; Aussel, C.; Salvucci, M.; Giboudeau, J. Action of Ornithine alpha- Ketoglutarate, ornithine hydrochloride, and calcium alphaketoglutarate on plasma amino-acid and hormonal patterns in healthy-subjects. J. Am. Coll. Nutr., 1990, 9, 2-12.
45. Lasnier, E.; CoudrayLucas, C.; LeBoucher, J.; Jardel, A.; Cynober, L. Ornithine alpha-ketoglutarate counteracts thymus involution and glutamine depletion in endotoxemic rats. Clin. Nutr., 1996, 15, 197-200.
46. Robinson, L.E.; Bussiere, F.I.; Le Boucher, J.; Farges, M.C.; Cynober, L.A.; Field, C.J.; Baracos, V.E. Amino acid nutrition and immune function in tumour-bearing rats: a comparison of glutamine-, arginine- and ornithine 2-oxoglutarate-supplemented diets. Clin. Sci., 1999, 97, 657-669.
47. Cynober, L.A. Understanding the pathological mechanisms underlying protein breakdown for new therapeutic strategies. Nutrition, 1995, 11, 398-398.
48. RochArveiller, M.; Tissot, M.; CoudrayLucas, C.; Fontagne, J.; LeBoucher, J.; Giroud, J.P.; Cynober, L. Immunomodulatory effects of ornithine alpha-ketoglutarate in rats with burn injuries. Arch. Surg-Chicago, 1996, 131, 718-723.
49. Schlegel, L.; Coudray-Lucas, C.; Barbut, F.; Le Boucher, J.; Jardel, A.; Zarrabian, S.; Cynober, L. Bacterial dissemination and metabolic changes in rats induced by endotoxemia following intestinal E-coli overgrowth are reduced by ornithine alphaketoglutarate administration. J. Nutr., 2000, 130, 2897-2902.
50. Rzeski, W.; Walczak, K.; Juszczak, M.; Langner, E.; Pozarowski, P.; Kandefer-Szerszen, M.; Pierzynowski, S.G. Alpha-ketoglutarate (AKG) inhibits proliferation of colon adenocarcinoma cells in normoxic conditions. Scand. J. Gastroenterol., 2012, 47, 565-571.
51. Radzki, R.P.; Bienko, M.; Pierzynowski, S.G. Anti-osteopenic effect of alpha-ketoglutarate sodium salt in ovariectomized rats. J. Bone Miner. Metab., 2012, 30, 651-659.
52. Puntel, R.L.; Roos, D.H.; Grotto, D.; Garcia, S.C.; Nogucira, C.W.; Teixeira Rocha, J.B. Antioxidant properties of Krebs cycle intermediates against malonate pro-oxidant activity in vitro: A comparative study using the colorimetric method and HPLC analysis to determine malondialdehyde in rat. Life Sci., 2007, 81, 51-62.
53. Velvizhi, S.; Dakshayani, K.B.; Subramanian, P. Effects of alphaketoglutarate on antioxidants and lipid peroxidation products in rats treated with ammonium acetate. Nutrition, 2002, 18, 747-750.
54. Niemiec, T.; Sikorska, J.; Harrison, A.; Szmidt, M.; Sawosz, E.; Wirth-Dzieciolowska, E.; Wilczak, J.; Pierzynowski, S. Alpha- Ketoglutarate Stabilizes Redox Homeostasis and Improves Arterial Elasticity in Aged Mice. J. Physiol. Pharmacol., 2011, 62, 37-43.
55. Valdivia, A.; Perez-Alvarez, S.; Aroca-Aguilar, J.D.; Ikuta, I.; Jordan, J. Superoxide dismutases: a physiopharmacological update. J. Physiol. Biochem., 2009, 65, 195-208.
56. Velvizhi, S.; Nagalashmi, T.; Essa, M.M.; Dakshayani, K.B.; Subramanian, P. Effects of alpha-ketoglutarate on lipid peroxidation and antioxidant status during chronic ethanol administration in Wistar rats. Pol. J. Pharmacol., 2002, 54, 231- 236.
57. Sokolowska, M.; Oleszek, A.; Wlodek, L. Protective effect of alpha-keto acids on the oxidative hemolysis. Pol. J. Pharmacol., 1999, 51, 429-434.
58. Desagher, S.; Glowinski, J.; Premont, J. Pyruvate protects neurons against hydrogen peroxide-induced toxicity. J. Neurosci., 1997, 17, 9060-9067.
59. Ali, R.; Mittal, G.; Sultana, S.; Bhatnagar, A. Ameliorative potential of alpha-ketoglutaric acid (AKG) on acute lung injuries induced by ammonia inhalation in rats. Exp. Lung Res., 2012, 38, 435-444.
60. Mullen, A.R.; Hu, Z.; Shi, X.; Jiang, L.; Boroughs, L.K.; Kovacs, Z.; Boriack, R.; Rakheja, D.; Sullivan, L.B.; Linehan, W.M.; et al. Oxidation of alpha-ketoglutarate is required for reductive carboxylation in cancer cells with mitochondrial defects. Cell Rep., 2014, 7, 1679-1690.
61. Tatara, M.R.; Brodzki, A.; Krupski, W.; Sliwa, E.; Silmanowicz, P.; Majcher, P.; Pierzynowski, S.G.; Studzinski, T. Effects of alpha-ketoglutarate on bone homeostasis and plasma amino acids in turkeys. Poul. Sci., 2005, 84, 1604-1609.
62. Tatara, M.R.; Krupski, W.; Sliwa, E.; Majcher, P.; Pierzynowski, S.G.; Studzinski, T. Effects of alpha-ketoglutarate (AKG) administration to pregnant sows on femur properties in offspring at slaughter. Bone, 2005, 36, S392-S393.
63. Hou, Y.Q.; Yao, K.; Wang, L.; Ding, B.Y.; Fu, D.B.; Liu, Y.L.; Zhu, H.L.; Liu, J.; Li, Y.T.; Kang, P., et al. Effects of alphaketoglutarate on energy status in the intestinal mucosa of weaned piglets chronically challenged with lipopolysaccharide. Br. J. Nutr., 2011, 106, 357-363.
64. He, L.Q.; Yang, H.S.; Hou, Y.Q.; Li, T.J.; Fang, J.; Zhou, X.H.; Yin, Y.L.; Wu, L.; Nychoti, C.M.; Wu, G.Y. Effects of dietary Llysine intake on the intestinal mucosa and expression of CAT genes in weaned piglets. Amino Acids, 2013, 45, 383-391.
65. Zhang, H.L.; Ji, S.K.; Chen, Y.; Yang, B.; Xu, X.L.; Hu, C.J. Effect of α-ketoglutaric acid on in vitro gas production, ruminal fermentation, and bacterial diversity. Anim. Feed Sci. Tech., 2011, 170, 291-296.
66. Wu, G. Functional amino acids in growth, reproduction and health. Adv. Nutr., 2010, 1, 31-37.
67. Wu, G. Functional amino acids in nutrition and health. Amino Acids, 2013, 45, 407-411.
68. Wu, G.; Wu, Z.L.; Dai, Z.L.; Yang, Y.; Wang, W.W.; Liu, C.; Wang, B.; Wang, J.J.; Yin, Y.L. Dietary requirements of "nutritionally nonessential amino acids" by animals and humans. Amino Acids, 2013, 44, 1107-1113.
69. Wang, W.W.; Wu, Z.L.; Dai, Z.L.; Yang, Y.; Wang, J.J.; Wu, G. Glycine metabolism in animals and humans: implications for nutrition and health. Amino Acids, 2013, 45, 463-477.
70. Wu, G.; Bazer, F.W.; Dai, Z.L.; Li, D.F.; Wang, J.J.; Wu, Z.L. Amino acid nutrition in animals: protein synthesis and beyond. Annu. Rev. Anim. Biosci., 2014, 2, 387-417.
71. Hou, Y.Q.; Wang, L.; Yi, D.; Wu, G. N-acetylcysteine and intestinal health: a focus on mechanisms of its actions. Front. Biosci., 2015, 20, 872-891.