title: Genetic or nutritional disorders in homocysteine or folate metabolism increase protein N-homocysteinylation in mice.
abstract: Genetic disorders of homocysteine (Hcy) or folate metabolism or high-methionine diets elevate plasma Hcy and its atherogenic metabolite Hcy-thiolactone. In humans, severe hyperhomocysteinemia due to genetic alterations in cystathionine beta-synthase (Cbs) or methylenetetrahydrofolate reductase (Mthfr) results in neurological abnormalities and premature death from vascular complications. In mouse models, dietary or genetic hyperhomocysteinemia results in liver or brain pathological changes and accelerates atherosclerosis. Hcy-thiolactone has the ability to form isopeptide bonds with protein lysine residues, which generates modified proteins (N-Hcy-protein) with autoimmunogenic and prothrombotic properties. Our aim was to determine how N-Hcy-protein levels are affected by genetic or nutritional disorders in Hcy or folate metabolism in mice. We found that plasma N-Hcy-protein was elevated 10-fold in mice fed a high-methionine diet compared with the animals fed a normal commercial diet. We also found that inactivation of Cbs, Mthfr, or the proton-coupled folate transporter (Pcft) gene resulted in a 10- to 30-fold increase in plasma or serum N-Hcy-protein levels. Liver N-Hcy-protein was elevated 3.4-fold in severely and 11-fold in extremely hyperhomocysteinemic Cbs-deficient mice, 3.6-fold in severely hyperhomocysteinemic Pcft mice, but was not elevated in mildly hyperhomocysteinemic Mthfr-deficient animals, suggesting that mice have a capacity to prevent accumulation of N-Hcy-protein in their organs. These findings provide evidence that N-Hcy-protein is an important metabolite associated with Hcy pathophysiology in the mouse.
authors.affiliation: Department of Microbiology and Molecular Genetics, UMDNJ-New Jersey Medical School, International Center for Public Health, 225 Warren St., Newark, NJ 07101-1709, USA. jakubows@umdnj.edu
authors.forename: Hieronim
authors.initials: H
authors.lastname: Jakubowski
authors.forename: Joanna
authors.initials: J
authors.lastname: Perla-Kaján
authors.forename: Richard H
authors.initials: RH
authors.lastname: Finnell
authors.forename: Robert M
authors.initials: RM
authors.lastname: Cabrera
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Sapna
authors.initials: S
authors.lastname: Gupta
authors.forename: Warren D
authors.initials: WD
authors.lastname: Kruger
authors.forename: Jan P
authors.initials: JP
authors.lastname: Kraus
authors.forename: Diana M
authors.initials: DM
authors.lastname: Shih
mesh_terms: D000818:Animals; D003541:Cystathionine beta-Synthase / Q000235:genetics / Q000378:metabolism; D004032:Diet; D005492:Folic Acid / Q000378:metabolism*; D006710:Homocysteine / Q000031:analogs & derivatives / Q000378:metabolism*; D006801:Humans; D020138:Hyperhomocysteinemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D008715:Methionine / Q000008:administration & dosage / Q000378:metabolism; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D026901:Membrane Transport Proteins; D006710:Homocysteine; D005492:Folic Acid; D008715:Methionine; C007957:homocysteine thiolactone; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D003541:Cystathionine beta-Synthase