PMID- 17971455
OWN - NLM
STAT- MEDLINE
DCOM- 20080220
LR  - 20211020
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 282
IP  - 51
DP  - 2007 Dec 21
TI  - Hypermethylation of Fads2 and altered hepatic fatty acid and phospholipid 
      metabolism in mice with hyperhomocysteinemia.
PG  - 37082-90
AB  - 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.
FAU - Devlin, Angela M
AU  - Devlin AM
AD  - Nutrition Research Program, Department of Pediatrics, Child & Family Research 
      Institute, University of British Columbia, Vancouver V6H 3N1, Canada. 
      angela.devlin@ubc.ca
FAU - Singh, Ranji
AU  - Singh R
FAU - Wade, Rachel E
AU  - Wade RE
FAU - Innis, Sheila M
AU  - Innis SM
FAU - Bottiglieri, Teodoro
AU  - Bottiglieri T
FAU - Lentz, Steven R
AU  - Lentz SR
LA  - eng
GR  - R01 HL063943/HL/NHLBI NIH HHS/United States
GR  - HL 62984/HL/NHLBI NIH HHS/United States
GR  - HL63943/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20071030
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Fatty Acids)
RN  - 0 (Phosphatidylcholines)
RN  - 0 (Phosphatidylethanolamines)
RN  - 39382-08-6 (phosphatidylethanolamine)
RN  - 7LP2MPO46S (S-Adenosylmethionine)
RN  - 979-92-0 (S-Adenosylhomocysteine)
RN  - EC 1.14.19.3 (Linoleoyl-CoA Desaturase)
RN  - EC 2.1.1.17 (Phosphatidylethanolamine N-Methyltransferase)
RN  - EC 4.2.1.22 (Cystathionine beta-Synthase)
SB  - IM
MH  - Animals
MH  - Cystathionine beta-Synthase/genetics/metabolism
MH  - *DNA Methylation
MH  - Fatty Acids/*biosynthesis/genetics
MH  - Gene Silencing
MH  - Heterozygote
MH  - Hyperhomocysteinemia/chemically induced/*enzymology/genetics/pathology
MH  - Linoleoyl-CoA Desaturase/*biosynthesis
MH  - Lipid Metabolism/genetics
MH  - Liver/*enzymology/pathology
MH  - Mice
MH  - Phosphatidylcholines/*biosynthesis/genetics
MH  - Phosphatidylethanolamine N-Methyltransferase/genetics/metabolism
MH  - Phosphatidylethanolamines/genetics/metabolism
MH  - *Promoter Regions, Genetic
MH  - S-Adenosylhomocysteine/metabolism
MH  - S-Adenosylmethionine/metabolism
EDAT- 2007/11/01 09:00
MHDA- 2008/02/21 09:00
CRDT- 2007/11/01 09:00
PHST- 2007/11/01 09:00 [pubmed]
PHST- 2008/02/21 09:00 [medline]
PHST- 2007/11/01 09:00 [entrez]
AID - S0021-9258(20)55232-0 [pii]
AID - 10.1074/jbc.M704256200 [doi]
PST - ppublish
SO  - J Biol Chem. 2007 Dec 21;282(51):37082-90. doi: 10.1074/jbc.M704256200. Epub 2007 
      Oct 30.