title: Hypermethylation of Fads2 and altered hepatic fatty acid and phospholipid metabolism in mice with hyperhomocysteinemia.
abstract: Alterations in lipid metabolism may play a role in the vascular pathology associated with hyperhomocysteinemia (HHcy). Homocysteine is linked to lipid metabolism through the methionine cycle and the synthesis of phosphatidylcholine (PC) by phosphatidylethanolamine (PE) methyltransferase, which is responsible for the synthesis of 20-40% of liver PC. The goal of the present study was to determine if the reduced methylation capacity in HHcy is associated with alterations in liver phospholipid and fatty acid metabolism. Mice heterozygous for disruption of cystathionine beta-synthase (Cbs+/-) fed a diet to induce HHcy (HH diet) had higher (p<0.001) plasma total homocysteine (30.8+/-4.4 microM, mean+/-S.E.) than C57BL/6 mice (Cbs+/+) fed the HH diet (7.0+/-1.1 microM) or Cbs+/+ mice fed a control diet (2.3+/-0.3 microM). Mild and moderate HHcy was accompanied by lower adenosylmethionine/adenosylhomocysteine ratios (p<0.05), higher PE (p<0.05) and PE/PC ratios (p<0.01), lower PE methyltransferase activity (p<0.001), and higher linoleic acid (p<0.05) and lower arachidonic acid (p<0.05) in PE. Mice with moderate HHcy also had higher linoleic acid and alpha-linolenic acid (p<0.05) and lower arachidonic acid and docosahexaenoic acid (p<0.05) in liver PC. The first step in the desaturation and elongation of linoleic acid and linolenic acid to arachidonic acid and docosahexaenoic acid, respectively, is catalyzed by Delta6-desaturase (encoded by Fads2). We found hypermethylation of the Fads2 promoter (p<0.01), lower Fads2 mRNA (p<0.05), and lower Delta6-desaturase activity (p<0.001) in liver from mice with HHcy. These findings suggest that methylation silencing of liver Fads2 expression and changes in liver fatty acids may contribute to the pathology of HHcy.
authors.affiliation: Nutrition Research Program, Department of Pediatrics, Child & Family Research Institute, University of British Columbia, Vancouver V6H 3N1, Canada. angela.devlin@ubc.ca
authors.forename: Angela M
authors.initials: AM
authors.lastname: Devlin
authors.forename: Ranji
authors.initials: R
authors.lastname: Singh
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Wade
authors.forename: Sheila M
authors.initials: SM
authors.lastname: Innis
authors.forename: Teodoro
authors.initials: T
authors.lastname: Bottiglieri
authors.forename: Steven R
authors.initials: SR
authors.lastname: Lentz
mesh_terms: D000818:Animals; D003541:Cystathionine beta-Synthase / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D005227:Fatty Acids / Q000096:biosynthesis* / Q000235:genetics; D020868:Gene Silencing; D006579:Heterozygote; D020138:Hyperhomocysteinemia / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D050602:Linoleoyl-CoA Desaturase / Q000096:biosynthesis*; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D010713:Phosphatidylcholines / Q000096:biosynthesis* / Q000235:genetics; D050918:Phosphatidylethanolamine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D010714:Phosphatidylethanolamines / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012435:S-Adenosylhomocysteine / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; C483858:phosphatidylethanolamine; D012436:S-Adenosylmethionine; D012435:S-Adenosylhomocysteine; D050602:Linoleoyl-CoA Desaturase; D050918:Phosphatidylethanolamine N-Methyltransferase; D003541:Cystathionine beta-Synthase