Hypermethylation of Fads2 and altered hepatic fatty acid and phospholipid metabolism in mice with hyperhomocysteinemia
Hypermethylation of Fads2 and altered hepatic fatty acid and phospholipid metabolism in mice with hyperhomocysteinemia
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DOI：
10.1074/jbc.m704256200
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发表时间：
2007-12-21
影响因子：
4.8
通讯作者：
Lentz, Steven R.
中科院分区：
文献类型：
--
作者：
Devlin, Angela M.;Singh, Ranji;Lentz, Steven R.
脂质代谢的改变可能在与高同型半胱氨酸血症（HHcy）相关的血管病理中起作用。同型半胱氨酸通过甲硫氨酸循环和磷脂酰乙醇胺（PE）甲基转移酶合成磷脂酰胆碱（PC）与脂质代谢相关，后者负责合成20-40%的肝脏PC。本研究的目的是确定HHCy甲基化能力的降低是否与肝脏磷脂和脂肪酸代谢的改变有关。喂食饮食以诱导HHcy（HH饮食）的胱硫醚β-合酶（Cbs（+/-））破坏杂合小鼠具有较高的（p < 0.001）血浆总同型半胱氨酸（30.8 +/-4.4 μ M，平均值+/- S.E.）与喂食HH饮食（7.0 +/-1.1 μ M）的C57 BL/6小鼠（Cbs（+/+））或喂食对照饮食（2.3 +/-0.3 μ M）的Cbs（+/+）小鼠相比。轻度和中度HHcy患者伴有较低的腺苷甲硫氨酸/腺苷同型半胱氨酸比值（p < 0.05）、较高的PE（p < 0.05）和PE/PC比值（p <0.01）、较低的PE甲基转移酶活性（p < 0.001）、较高的亚油酸（p < 0.05）和较低的花生四烯酸（p < 0.05）。中度高同型半胱氨酸小鼠肝PC中亚油酸和α-亚麻酸含量显著升高（p < 0.05），花生四烯酸和二十二碳六烯酸含量显著降低（p < 0.05）。亚油酸和亚麻酸分别去饱和和延伸为花生四烯酸和二十二碳六烯酸的第一步由Delta（6）-去饱和酶（由Fads 2编码）催化。我们发现HHcy小鼠肝脏中Fads 2启动子的高甲基化（p < 0.01）、较低的Fads 2 mRNA（p < 0.05）和较低的Δ（6）-去饱和酶活性（p < 0.001）。这些结果表明，肝脏Fads 2表达的甲基化沉默和肝脏脂肪酸的变化可能有助于HHcy的病理。
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 mu M, mean +/- S.E.) than C57BL/6 mice (Cbs(+/+)) fed the HH diet (7.0 +/- 1.1 mu M) or Cbs(+/+)mice fed a control diet (2.3 +/- 0.3 mu M). 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 Delta(6)-desaturase (encoded by Fads2). We found hypermethylation of the Fads2 promoter (p < 0.01), lower Fads2 mRNA ( p < 0.05), and lower Delta(6)-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.