Hypermethylation of Fads2 and altered hepatic fatty acid and phospholipid metabolism in mice with hyperhomocysteinemia

Angela M Devlin; Ranji Singh; Rachel E Wade; Sheila M Innis; Teodoro Bottiglieri; Steven R Lentz

doi:10.1074/jbc.M704256200

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Hypermethylation of Fads2 and altered hepatic fatty acid and phospholipid metabolism in mice with hyperhomocysteinemia

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Hypermethylation of Fads2 and altered hepatic fatty acid and phospholipid metabolism in mice with hyperhomocysteinemia

Angela M Devlin, Ranji Singh, Rachel E Wade, Sheila M Innis, Teodoro Bottiglieri and Steven R Lentz

The Journal of biological chemistry, Vol.282(51), pp.37082-37090

12/21/2007

DOI: 10.1074/jbc.M704256200

PMID: 17971455

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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.

S-Adenosylhomocysteine - metabolism

Liver - pathology

Liver - enzymology

Phosphatidylethanolamine N-Methyltransferase - metabolism

Phosphatidylcholines - biosynthesis

Phosphatidylethanolamine N-Methyltransferase - genetics

DNA Methylation

Fatty Acids - genetics

Lipid Metabolism - genetics

Cystathionine beta-Synthase - genetics

Hyperhomocysteinemia - enzymology

Promoter Regions, Genetic

Hyperhomocysteinemia - pathology

Gene Silencing

Cystathionine beta-Synthase - metabolism

Linoleoyl-CoA Desaturase - biosynthesis

Phosphatidylcholines - genetics

Animals

Heterozygote

Hyperhomocysteinemia - genetics

Mice

Phosphatidylethanolamines - genetics

Phosphatidylethanolamines - metabolism

Hyperhomocysteinemia - chemically induced

S-Adenosylmethionine - metabolism

Fatty Acids - biosynthesis

Details

Title: Subtitle: Hypermethylation of Fads2 and altered hepatic fatty acid and phospholipid metabolism in mice with hyperhomocysteinemia
Creators: Angela M Devlin - Nutrition Research Program, Department of Pediatrics, Child & Family Research Institute, University of British Columbia, Vancouver V6H 3N1, Canada. angela.devlin@ubc.ca
Ranji Singh
Rachel E Wade
Sheila M Innis
Teodoro Bottiglieri
Steven R Lentz
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.282(51), pp.37082-37090
DOI: 10.1074/jbc.M704256200
PMID: 17971455
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Grant note: HL63943 / NHLBI NIH HHS R01 HL063943 / NHLBI NIH HHS HL 62984 / NHLBI NIH HHS
Language: English
Date published: 12/21/2007
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
Record Identifier: 9984094541202771

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