| The nutrigenetics of hyperhomocysteinemia: quantitative proteomics reveals differences in the methionine cycle enzymes of gene-induced versus diet-induced hyperhomocysteinemia. | |
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MedLine Citation:
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PMID: 20008833 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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 beta-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 < or = 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 up-regulated. S-Adenosylhomocysteine hydrolase increased in response to genotype and/or diet, whereas glycine N-methyltransferase 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. |
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Authors:
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Patricia M DiBello; Sanjana Dayal; Suma Kaveti; Dongmei Zhang; Michael Kinter; Steven R Lentz; Donald W Jacobsen |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2009-12-14 |
Journal Detail:
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Title: Molecular & cellular proteomics : MCP Volume: 9 ISSN: 1535-9484 ISO Abbreviation: Mol. Cell Proteomics Publication Date: 2010 Mar |
Date Detail:
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Created Date: 2010-02-25 Completed Date: 2010-07-13 Revised Date: 2012-01-12 |
Medline Journal Info:
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Nlm Unique ID: 101125647 Medline TA: Mol Cell Proteomics Country: United States |
Other Details:
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Languages: eng Pagination: 471-85 Citation Subset: IM |
Affiliation:
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Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adenosylhomocysteinase
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metabolism Animals Antioxidants / metabolism* Betaine-Homocysteine S-Methyltransferase / metabolism Cystathionine beta-Synthase / genetics* Diet / adverse effects* Glycine N-Methyltransferase / metabolism Homocysteine / metabolism* Hyperhomocysteinemia / chemically induced, enzymology*, genetics Liver / enzymology* Methionine / metabolism* Mice Mice, Inbred C57BL Mice, Transgenic Nutrigenomics* Peroxiredoxins / metabolism Proteomics Urea / metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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HL 063943/HL/NHLBI NIH HHS; HL 52234/HL/NHLBI NIH HHS; NS024621/NS/NINDS NIH HHS; R01 HL052234-11/HL/NHLBI NIH HHS; R01 HL063943-11/HL/NHLBI NIH HHS; R01 HL063943-12/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antioxidants; 454-28-4/Homocysteine; 57-13-6/Urea; 63-68-3/Methionine; EC 1.11.1.15/Peroxiredoxins; EC 2.1.1.20/Glycine N-Methyltransferase; EC 2.1.1.5/Betaine-Homocysteine S-Methyltransferase; EC 3.3.1.1/Adenosylhomocysteinase; EC 4.2.1.22/Cystathionine beta-Synthase |
| Comments/Corrections | |
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