The Nutrigenetics of Hyperhomocysteinemia

Abstract

Hyperhomocysteinemia has long been associated with atherosclerosis and thrombosis and is an independent risk factor for cardiovascular disease. Its causes include both genetic and environmental factors. Although homocysteine is produced in every cell as an intermediate of the methionine cycle, the liver contributes the major portion found in circulation, and fatty liver is a common finding in homocystinuric patients. To understand the spectrum of proteins and associated pathways affected by hyperhomocysteinemia, we analyzed the mouse liver proteome of gene-induced (cystathionine ␤-synthase (CBS)) and diet-induced (high methionine) hyperhomocysteinemic mice using two-dimensional difference gel electrophoresis and Ingenuity Pathway Analysis. Nine proteins were identified whose expression was significantly changed by 2-fold (p < 0.05) as a result of genotype, 27 proteins were changed as a result of diet, and 14 proteins were changed in response to genotype and diet. Importantly, three enzymes of the methionine cycle were upregulated. S-Adenosylhomocysteine hydrolase increased in response to genotype and/or diet, whereas glycine Nmethyltransferase and betaine-homocysteine methyltransferase only increased in response to diet. The antioxidant proteins peroxiredoxins 1 and 2 increased in wild-type mice fed the high methionine diet but not in the CBS mutants, suggesting a dysregulation in the antioxidant capacity of those animals. Furthermore, thioredoxin 1 decreased in both wild-type and CBS mutants on the diet but not in the mutants fed a control diet. Several urea cycle proteins increased in both diet groups; however, arginase 1 decreased in the CBS ؉/؊ mice fed the control diet. Pathway analysis identified the retinoid X receptor signaling pathway as the top ranked network associated with the CBS ؉/؊ genotype, whereas xenobiotic metabolism and the NRF2-mediated oxidative stress response were associated with the high methionine diet. Our results show that hyperhomocysteinemia, whether caused by a genetic mutation or diet, alters the abundance of several liver proteins involved in homocysteine/methionine metabolism, the urea cycle, and antioxidant defense. Molecular & Cellular Proteomics 9:471-485, 2010.

Hypermethylation: Causes and Consequences in Skeletal Muscle Myopathy

“…In addition, Hcy can also form Hcy-thiolactone and acetylates free amino groups in proteins, which further intensify the exaggerated oxidative stress condition [Hayden and Tyagi, 2004]. DiBello et al [2010] showed that proteins (PRDX1, PRDX2, and HSP90AA) which are produce as a response to oxidative stress was significantly upregulated in liver during HHcy [Mishra et al, 2010].…”

Associação da deficiência de ácido fólico com alterações patológicas e estratégias para sua prevenção: uma visão crítica

“…Os tetra-hidrofolatos reduzidos são necessários para o processo de divisão celular e para assegurar a síntese do S-adenosilmetionina (SAM), o maior doador celular de grupamento metil para as reações de metilação 2 .…”

“…A metilação do ácido desoxirribonucleico (DNA) está relacionada com o controle da expressão gênica e manutenção da conformação e integridade dos cromossomos 2 . As reações de metilação também são vitais para prevenir o aumento das concentrações plasmáticas da homocisteína (Hcy), quadro denominado de Hiper-homocisteinemia (Hhcy), considerado um marcador das Doenças Cardiovasculares (DCV) 3,4 .…”

“…Uma vez no interior da célula, o 5-metil THF é demetilado e convertido em tetra-hidrofolato-poliglutamato pela ação da enzima folilpoliglutamato sintase. Antes de alcançarem a circulação, os poliglutamatos são reconvertidos em monoglutamatos pela enzima poliglutamato hidrolase 2 .…”

Glycine Betaine Recognition through Cation−π Interactions in Crystal Structures of Glycine Betaine Complexes with C-Ethyl-pyrogallol[4]arene and C-Ethyl-resorcin[4]arene as Receptors

“…Betaine-homocysteine-S-methyltransferase (E.C. 2.1.1.5) requires betaine together with zinc ion as an important methyl donor coenzyme for metabolizing homocysteine, which is one of the inductive factors of atherosclerosis, to methionine in liver and kidney of man and pig [4][5][6][7]. Betaine is a simple small molecule composed of a methylene group with a cationic trimethylammonium group and a carboxyl group at both ends.…”