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Reduced Expression and Methylation of Soat2 in Liver From Mice with Hyperhomocysteinemia.
Author(s) -
Devlin Angela M,
Singh Ranji,
Wade Rachel,
Boersma Heather,
Innis Sheila M
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a120-d
Subject(s) - cystathionine beta synthase , hyperhomocysteinemia , methylation , medicine , endocrinology , methionine , sterol o acyltransferase , homocysteine , cholesterol , dna methylation , biology , chemistry , methionine synthase , methylenetetrahydrofolate reductase , gene expression , biochemistry , gene , lipoprotein , amino acid , allele
Hyperhomocysteinemia (HHcy) is associated with alterations in liver lipid metabolism and this may contribute to the pathological effects of HHcy. The goal of this study was to determine if HHcy is associated with changes in liver cholesterol ester fatty acids and expression and methylation of the Soat2 gene. Soat2 encodes acyl‐coenzyme A:cholesterol acyltransferase 2 (ACAT2), which functions to catalyze the reaction responsible for the intracellular esterification of cholesterol with acyl‐CoA molecules, with oleoyl‐CoA the preferred substrate. Mice heterozygous for disruption of the gene for cystathionine‐(‐synthase (Cbs +/−) and C57BL/6 mice (Cbs +/+) were fed a control diet or a high methionine/low folate (HH) diet to induce HHcy. Levels of Soat2 mRNA (p<0.05) and ACAT protein (p<0.001) in liver were lower in Cbs +/− mice fed the HH diet with higher plasma total homocysteine levels than Cbs +/+ mice fed the control diet (35.01±5.6 vs 2.21±0.6 (M, respectively). Given we have previously shown that HHcy is accompanied by reduced tissue methylation capacity and changes in gene‐specific DNA methylation, we determined the methylation status of Soat2. In silico searches identified a CpG‐rich region in the 5′ upstream portion of the Soat2 gene and found that this region was 50% less methylated in Cbs +/− mice fed the HH diet than in Cbs +/+ mice fed the control diet. Total levels of cholesterol ester in liver were not different in mice with HHcy but levels of oleic acid were lower (p<0.05) in cholesterol esters from Cbs+/− mice fed the HH diet than Cbs+/+ mice fed the control diet. These findings are the first to show reduced methylation and expression of the Soat2 gene in a mouse model of HHcy and suggest role for changes in liver cholesterol ester metabolism in the pathology of HHcy.