Nutr Res Pract.  2014 Feb;8(1):3-10.

Biological functions of histidine-dipeptides and metabolic syndrome

• Song BC
• Joo NS
• Aldini G
• Yeum KJ

Abstract

The rapid increase in the prevalence of metabolic syndrome, which is associated with a state of elevated systemic oxidative stress and inflammation, is expected to cause future increases in the prevalence of diabetes and cardiovascular diseases. Oxidation of polyunsaturated fatty acids and sugars produces reactive carbonyl species, which, due to their electrophilic nature, react with the nucleophilic sites of certain amino acids. This leads to formation of protein adducts such as advanced glycoxidation/lipoxidation end products (AGEs/ALEs), resulting in cellular dysfunction. Therefore, an effective reactive carbonyl species and AGEs/ALEs sequestering agent may be able to prevent such cellular dysfunction. There is accumulating evidence that histidine containing dipeptides such as carnosine (beta-alanyl-L-histidine) and anserine (beta-alanyl-methyl-L-histidine) detoxify cytotoxic reactive carbonyls by forming unreactive adducts and are able to reverse glycated protein. In this review, 1) reaction mechanism of oxidative stress and certain chronic diseases, 2) interrelation between oxidative stress and inflammation, 3) effective reactive carbonyl species and AGEs/ALEs sequestering actions of histidine-dipeptides and their metabolism, 4) effects of carnosinase encoding gene on the effectiveness of histidine-dipeptides, and 5) protective effects of histidine-dipeptides against progression of metabolic syndrome are discussed. Overall, this review highlights the potential beneficial effects of histidine-dipeptides against metabolic syndrome. Randomized controlled human studies may provide essential information regarding whether histidine-dipeptides attenuate metabolic syndrome in humans.

Keyword

Carnosine; anserine; metabolic syndrome; CNDP-1 genotype; advanced glycoxidation end products (AGEs)

MeSH Terms

Amino Acids
Anserine
Carbohydrates
Cardiovascular Diseases
Carnosine
Chronic Disease
Dipeptides
Fatty Acids, Unsaturated
Histidine
Humans
Inflammation
Metabolism
Oxidative Stress
Prevalence
Sequestering Agents
Amino Acids
Anserine
Carbohydrates
Carnosine
Dipeptides
Fatty Acids, Unsaturated
Histidine
Sequestering Agents

Figure

• 

  Fig. 1 Structures of reactive carbonyl species derived from (A) lipid peroxidation and (B) sugar oxidation

• 

  Fig. 2 Mesomeric equilibrium of the reactivity carbonyl species, 4-hydroxy-trans-2-nonenal, producing a strong electrophilic center

• 

  Fig. 3 Reactive carbonyl species produced by the oxidation of polyunsaturated fatty acid and sugars react with protein, producing advanced glycoxidation and lipoxidation end products (AGEs/ALEs), which can cause irreversible cellular dysfunction. PUFA, polyunsaturated fatty acids; AGEs, advanced glycoxidation end products; ALEs, advanced lipoxidation end products

• 

  Fig. 4 Structures of histidine-dipeptides, carnosine and anserine

• 

  Fig. 5 Cytotoxic reactive carbonyl species sequestering action of the histidine-dipeptides (i.e. carnosine). HNE, 4-hydroxy-trans-2-nonenal

• 

  Fig. 6 Histidine-dipeptides can act at two key points of the oxidative stress cascade: by removing reactive oxygen species before producing cytotoxic reactive carbonyl species, and by directly sequestering reactive carbonyl species. HD, histidine-dipeptides; RCS, reactive carbonyl species; AGEs, advanced glycoxidation products, ALEs, advanced lipoxidation end products

Reference

1. Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, Fruchart JC, James WP, Loria CM, Smith SC Jr. International Diabetes Federation Task Force on Epidemiology and Prevention. Hational Heart, Lung, and Blood Institute. American Heart Association. World Heart Federation. International Atherosclerosis Society. International Association for the Study of Obesity. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009; 120:1640–1645.

2. Ford ES, Giles WH, Mokdad AH. Increasing prevalence of the metabolic syndrome among U.S. adults. Diabetes Care. 2004; 27:2444–2449.

3. Lim S, Shin H, Song JH, Kwak SH, Kang SM, Won Yoon J, Choi SH, Cho SI, Park KS, Lee HK, Jang HC, Koh KK. Increasing prevalence of metabolic syndrome in Korea: the Korean National Health and Nutrition Examination Survey for 1998-2007. Diabetes Care. 2011; 34:1323–1328.

4. Ervin RB. Prevalence of metabolic syndrome among adults 20 years of age and over, by sex, age, race and ethnicity, and body mass index: United States, 2003-2006. Natl Health Stat Report. 2009; 1–7.

5. Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, Nakayama O, Makishima M, Matsuda M, Shimomura I. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest. 2004; 114:1752–1761.

6. Dandona P, Mohanty P, Ghanim H, Aljada A, Browne R, Hamouda W, Prabhala A, Afzal A, Garg R. The suppressive effect of dietary restriction and weight loss in the obese on the generation of reactive oxygen species by leukocytes, lipid peroxidation, and protein carbonylation. J Clin Endocrinol Metab. 2001; 86:355–362.

7. Caimi G, Hopps E, Noto D, Canino B, Montana M, Lucido D, Lo Presti R, Averna MR. Protein oxidation in a group of subjects with metabolic syndrome. Diabetes Metab Syndr. 2013; 7:38–41.

8. Festa A, D'Agostino R Jr, Williams K, Karter AJ, Mayer-Davis EJ, Tracy RP, Haffner SM. The relation of body fat mass and distribution to markers of chronic inflammation. Int J Obes Relat Metab Disord. 2001; 25:1407–1415.

9. Ford ES, Schulze MB, Pischon T, Bergmann MM, Joost HG, Boeing H. Metabolic syndrome and risk of incident diabetes: findings from the European Prospective Investigation into Cancer and Nutrition-Potsdam Study. Cardiovasc Diabetol. 2008; 7:35.

10. Grundy SM. A constellation of complications: the metabolic syndrome. Clin Cornerstone. 2005; 7:36–45.

11. Carini M, Aldini G, Facino RM. Mass spectrometry for detection of 4-hydroxy-trans-2-nonenal (HNE) adducts with peptides and proteins. Mass Spectrom Rev. 2004; 23:281–305.

12. Pedchenko VK, Chetyrkin SV, Chuang P, Ham AJ, Saleem MA, Mathieson PW, Hudson BG, Voziyan PA. Mechanism of perturbation of integrin-mediated cell-matrix interactions by reactive carbonyl compounds and its implication for pathogenesis of diabetic nephropathy. Diabetes. 2005; 54:2952–2960.

13. Uchida K. Role of reactive aldehyde in cardiovascular diseases. Free Radic Biol Med. 2000; 28:1685–1696.

14. Poli G, Schaur RJ. 4-Hydroxynonenal in the pathomechanisms of oxidative stress. IUBMB Life. 2000; 50:315–321.

15. Dalle-Donne I, Aldini G, Carini M, Colombo R, Rossi R, Milzani A. Protein carbonylation, cellular dysfunction, and disease progression. J Cell Mol Med. 2006; 10:389–406.

16. Harcourt BE, Sourris KC, Coughlan MT, Walker KZ, Dougherty SL, Andrikopoulos S, Morley AL, Thallas-Bonke V, Chand V, Penfold SA, de Courten MP, Thomas MC, Kingwell BA, Bierhaus A, Cooper ME, de Courten B, Forbes JM. Targeted reduction of advanced glycation improves renal function in obesity. Kidney Int. 2011; 80:190–198.

17. Singh DK, Winocour P, Farrington K. Oxidative stress in early diabetic nephropathy: fueling the fire. Nat Rev Endocrinol. 2011; 7:176–184.

18. Ghanem AA, Elewa A, Arafa LF. Pentosidine and N-carboxymethyl-lysine: biomarkers for type 2 diabetic retinopathy. Eur J Ophthalmol. 2011; 21:48–54.

19. Hirata K, Kubo K. Relationship between blood levels of N-carboxymethyl-lysine and pentosidine and the severity of microangiopathy in type 2 diabetes. Endocr J. 2004; 51:537–544.

20. Dworacka M, Winiarska H, Szymańska M, Szczawińska K, Wierusz-Wysocka B. Serum N-epsilon-(carboxymethyl)lysine is elevated in nondiabetic coronary heart disease patients. J Basic Clin Physiol Pharmacol. 2002; 13:201–213.

21. Ramasamy R, Yan SF, Schmidt AM. The diverse ligand repertoire of the receptor for advanced glycation endproducts and pathways to the complications of diabetes. Vascul Pharmacol. 2012; 57:160–167.

22. Bierhaus A, Nawroth PP. Multiple levels of regulation determine the role of the receptor for AGE (RAGE) as common soil in inflammation, immune responses and diabetes mellitus and its complications. Diabetologia. 2009; 52:2251–2263.

23. Barlovic DP, Soro-Paavonen A, Jandeleit-Dahm KA. RAGE biology, atherosclerosis and diabetes. Clin Sci (Lond). 2011; 121:43–55.

24. Coughlan MT, Thorburn DR, Penfold SA, Laskowski A, Harcourt BE, Sourris KC, Tan AL, Fukami K, Thallas-Bonke V, Nawroth PP, Brownlee M, Bierhaus A, Cooper ME, Forbes JM. RAGE-induced cytosolic ROS promote mitochondrial superoxide generation in diabetes. J Am Soc Nephrol. 2009; 20:742–752.

25. Aldini G, Vistoli G, Stefek M, Chondrogianni N, Grune T, Sereikaite J, Sadowska-Bartosz I, Bartosz G. Molecular strategies to prevent, inhibit, and degrade advanced glycoxidation and advanced lipoxidation end products. Free Radic Res. 2013; 47:Suppl 1. 93–137.

26. Quinn PJ, Boldyrev AA, Formazuyk VE. Carnosine: its properties, functions and potential therapeutic applications. Mol Aspects Med. 1992; 13:379–444.

27. Park YJ, Volpe SL, Decker EA. Quantitation of carnosine in humans plasma after dietary consumption of beef. J Agric Food Chem. 2005; 53:4736–4739.

28. Chan KM, Decker EA. Endogenous skeletal muscle antioxidants. Crit Rev Food Sci Nutr. 1994; 34:403–426.

29. Gil-Agustí M, Esteve-Romero J, Carda-Broch S. Anserine and carnosine determination in meat samples by pure micellar liquid chromatography. J Chromatogr A. 2008; 1189:444–450.

30. Horinishi H, Grillo M, Margolis FL. Purification and characterization of carnosine synthetase from mouse olfactory bulbs. J Neurochem. 1978; 31:909–919.

31. Teufel M, Saudek V, Ledig JP, Bernhardt A, Boularand S, Carreau A, Cairns NJ, Carter C, Cowley DJ, Duverger D, Ganzhorn AJ, Guenet C, Heintzelmann B, Laucher V, Sauvage C, Smirnova T. Sequence identification and characterization of human carnosinase and a closely related non-specific dipeptidase. J Biol Chem. 2003; 278:6521–6531.

32. Yeum KJ, Orioli M, Regazzoni L, Carini M, Rasmussen H, Russell RM, Aldini G. Profiling histidine dipeptides in plasma and urine after ingesting beef, chicken or chicken broth in humans. Amino Acids. 2010; 38:847–858.

33. Kohen R, Yamamoto Y, Cundy KC, Ames BN. Antioxidant activity of carnosine, homocarnosine, and anserine present in muscle and brain. Proc Natl Acad Sci U S A. 1988; 85:3175–3179.

34. Kang JH, Kim KS, Choi SY, Kwon HY, Won MH, Kang TC. Carnosine and related dipeptides protect human ceruloplasmin against peroxyl radical-mediated modification. Mol Cells. 2002; 13:498–502.

35. Egorov SYu, Kurella EG, Boldyrev AA, Krasnovsky AA Jr. Quenching of singlet molecular oxygen by carnosine and related antioxidants. Monitoring 1270-nm phosphorescence in aqueous media. Biochem Mol Biol Int. 1997; 41:687–694.

36. Brownson C, Hipkiss AR. Carnosine reacts with a glycated protein. Free Radic Biol Med. 2000; 28:1564–1570.

37. Carini M, Aldini G, Beretta G, Arlandini E, Facino RM. Acrolein-sequestering ability of endogenous dipeptides: characterization of carnosine and homocarnosine/acrolein adducts by electrospray ionization tandem mass spectrometry. J Mass Spectrom. 2003; 38:996–1006.

38. Aldini G, Carini M, Beretta G, Bradamante S, Facino RM. Carnosine is a quencher of 4-hydroxy-nonenal: through what mechanism of reaction? Biochem Biophys Res Commun. 2002; 298:699–706.

39. Miller ER 3rd, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2005; 142:37–46.

40. Lawson KA, Wright ME, Subar A, Mouw T, Hollenbeck A, Schatzkin A, Leitzmann MF. Multivitamin use and risk of prostate cancer in the National Institutes of Health-AARP Diet and Health Study. J Natl Cancer Inst. 2007; 99:754–764.

41. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Cochrane Database Syst Rev. 2012; 3:CD007176.

42. Rietjens IM, Boersma MG, Haan Ld, Spenkelink B, Awad HM, Cnubben NH, van Zanden JJ, Woude Hv, Alink GM, Koeman JH. The pro-oxidant chemistry of the natural antioxidants vitamin C, vitamin E, carotenoids and flavonoids. Environ Toxicol Pharmacol. 2002; 11:321–333.

43. Veeramachaneni S, Ausman LM, Choi SW, Russell RM, Wang XD. High dose lycopene supplementation increases hepatic cytochrome P4502E1 protein and inflammation in alcohol-fed rats. J Nutr. 2008; 138:1329–1335.

44. van Helden YG, Keijer J, Knaapen AM, Heil SG, Briedé JJ, van Schooten FJ, Godschalk RW. Beta-carotene metabolites enhance inflammation-induced oxidative DNA damage in lung epithelial cells. Free Radic Biol Med. 2009; 46:299–304.

45. Hipkiss AR, Michaelis J, Syrris P. Non-enzymatic glycosylation of the dipeptide L-carnosine, a potential anti-protein-cross-linking agent. FEBS Lett. 1995; 371:81–85.

46. Sato M, Karasawa N, Shimizu M, Morimatsu F, Yamada R. Safety evaluation of chicken breast extract containing carnosine and anserine. Food Chem Toxicol. 2008; 46:480–489.

47. Gardner ML, Illingworth KM, Kelleher J, Wood D. Intestinal absorption of the intact peptide carnosine in man, and comparison with intestinal permeability to lactulose. J Physiol. 1991; 439:411–422.

48. Son DO, Satsu H, Kiso Y, Shimizu M. Characterization of carnosine uptake and its physiological function in human intestinal epithelial Caco-2 cells. Biofactors. 2004; 21:395–398.

49. Cahill LE, Fontaine-Bisson B, El-Sohemy A. Functional genetic variants of glutathione S-transferase protect against serum ascorbic acid deficiency. Am J Clin Nutr. 2009; 90:1411–1417.

50. Milman U, Blum S, Shapira C, Aronson D, Miller-Lotan R, Anbinder Y, Alshiek J, Bennett L, Kostenko M, Landau M, Keidar S, Levy Y, Khemlin A, Radan A, Levy AP. Vitamin E supplementation reduces cardiovascular events in a subgroup of middle-aged individuals with both type 2 diabetes mellitus and the haptoglobin 2-2 genotype: a prospective double-blinded clinical trial. Arterioscler Thromb Vasc Biol. 2008; 28:341–347.

51. Janssen B, Hohenadel D, Brinkkoetter P, Peters V, Rind N, Fischer C, Rychlik I, Cerna M, Romzova M, de Heer E, Baelde H, Bakker SJ, Zirie M, Rondeau E, Mathieson P, Saleem MA, Meyer J, Köppel H, Sauerhoefer S, Bartram CR, Nawroth P, Hammes HP, Yard BA, Zschocke J, van der Woude FJ. Carnosine as a protective factor in diabetic nephropathy: association with a leucine repeat of the carnosinase gene CNDP1. Diabetes. 2005; 54:2320–2327.

52. Freedman BI, Hicks PJ, Sale MM, Pierson ED, Langefeld CD, Rich SS, Xu J, McDonough C, Janssen B, Yard BA, van der Woude FJ, Bowden DW. A leucine repeat in the carnosinase gene CNDP1 is associated with diabetic end-stage renal disease in European Americans. Nephrol Dial Transplant. 2007; 22:1131–1135.

53. Stadtman ER. Metal ion-catalyzed oxidation of proteins: biochemical mechanism and biological consequences. Free Radic Biol Med. 1990; 9:315–325.

54. McGrath LT, McGleenon BM, Brennan S, McColl D, McILroy S, Passmore AP. Increased oxidative stress in Alzheimer's disease as assessed with 4-hydroxynonenal but not malondialdehyde. QJM. 2001; 94:485–490.

55. Neuhouser ML, Wassertheil-Smoller S, Thomson C, Aragaki A, Anderson GL, Manson JE, Patterson RE, Rohan TE, van Horn L, Shikany JM, Thomas A, LaCroix A, Prentice RL. Multivitamin use and risk of cancer and cardiovascular disease in the Women's Health Initiative cohorts. Arch Intern Med. 2009; 169:294–304.

56. Aldini G, Granata P, Orioli M, Santaniello E, Carini M. Detoxification of 4-hydroxynonenal (HNE) in keratinocytes: characterization of conjugated metabolites by liquid chromatography/electrospray ionization tandem mass spectrometry. J Mass Spectrom. 2003; 38:1160–1168.

57. Seidler NW, Yeargans GS, Morgan TG. Carnosine disaggregates glycated alpha-crystallin: an in vitro study. Arch Biochem Biophys. 2004; 427:110–115.

58. Seidler NW. Carnosine prevents the glycation-induced changes in electrophoretic mobility of aspartate aminotransferase. J Biochem Mol Toxicol. 2000; 14:215–220.

59. Aldini G, Orioli M, Rossoni G, Savi F, Braidotti P, Vistoli G, Yeum KJ, Negrisoli G, Carini M. The carbonyl scavenger carnosine ameliorates dyslipidaemia and renal function in Zucker obese rats. J Cell Mol Med. 2011; 15:1339–1354.

60. Aldini G, Regazzoni L, Orioli M, Rimoldi I, Facino RM, Carini M. A tandem MS precursor-ion scan approach to identify variable covalent modification of albumin Cys34: a new tool for studying vascular carbonylation. J Mass Spectrom. 2008; 43:1470–1481.

61. Aldini G, Vistoli G, Regazzoni L, Gamberoni L, Facino RM, Yamaguchi S, Uchida K, Carini M. Albumin is the main nucleophilic target of human plasma: a protective role against pro-atherogenic electrophilic reactive carbonyl species? Chem Res Toxicol. 2008; 21:824–835.

62. Okada K, Wangpoengtrakul C, Osawa T, Toyokuni S, Tanaka K, Uchida K. 4-Hydroxy-2-nonenal-mediated impairment of intracellular proteolysis during oxidative stress. Identification of proteasomes as target molecules. J Biol Chem. 1999; 274:23787–23793.

63. Mistry N, Bevan RJ, Cooke MS, Evans MD, Halligan EP, Lowes DA, Nichol K, Lunec J. Antiserum detection of reactive carbonyl species-modified DNA in human colonocytes. Free Radic Res. 2008; 42:344–353.

64. Roberts MJ, Wondrak GT, Laurean DC, Jacobson MK, Jacobson EL. DNA damage by carbonyl stress in human skin cells. Mutat Res. 2003; 522:45–56.

65. Gallant S, Semyonova M, Yuneva M. Carnosine as a potential anti-senescence drug. Biochemistry (Mosc). 2000; 65:866–868.

66. Hipkiss AR. Glycation, ageing and carnosine: are carnivorous diets beneficial? Mech Ageing Dev. 2005; 126:1034–1039.

67. Lee YT, Hsu CC, Lin MH, Liu KS, Yin MC. Histidine and carnosine delay diabetic deterioration in mice and protect human low density lipoprotein against oxidation and glycation. Eur J Pharmacol. 2005; 513:145–150.

68. Kurata H, Fujii T, Tsutsui H, Katayama T, Ohkita M, Takaoka M, Tsuruoka N, Kiso Y, Ohno Y, Fujisawa Y, Shokoji T, Nishiyama A, Abe Y, Matsumura Y. Renoprotective effects of l-carnosine on ischemia/reperfusion-induced renal injury in rats. J Pharmacol Exp Ther. 2006; 319:640–647.

69. Nagai K, Niijima A, Yamano T, Otani H, Okumra N, Tsuruoka N, Nakai M, Kiso Y. Possible role of L-carnosine in the regulation of blood glucose through controlling autonomic nerves. Exp Biol Med (Maywood). 2003; 228:1138–1145.

70. Gualano B, Everaert I, Stegen S, Artioli GG, Taes Y, Roschel H, Achten E, Otaduy MC, Junior AH, Harris R, Derave W. Reduced muscle carnosine content in type 2, but not in type 1 diabetic patients. Amino Acids. 2012; 43:21–24.

71. Sauerhöfer S, Yuan G, Braun GS, Deinzer M, Neumaier M, Gretz N, Floege J, Kriz W, van der Woude F, Moeller MJ. L-carnosine, a substrate of carnosinase-1, influences glucose metabolism. Diabetes. 2007; 56:2425–2432.

72. Tsoi B, He RR, Yang DH, Li YF, Li XD, Li WX, Abe K, Kurihara H. Carnosine ameliorates stress-induced glucose metabolism disorder in restrained mice. J Pharmacol Sci. 2011; 117:223–229.

73. Chez MG, Buchanan CP, Aimonovitch MC, Becker M, Schaefer K, Black C, Komen J. Double-blind, placebo-controlled study of L-carnosine supplementation in children with autistic spectrum disorders. J Child Neurol. 2002; 17:833–837.