Biological functions of histidine-dipeptides and metabolic syndrome

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 (β-alanyl-L-histidine) and anserine (β-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.

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

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