The Development of a Metabolic Disease Phenotype in CTP: Phosphoethanolamine Cytidylyltransferase-deficient Mice
The Development of a Metabolic Disease Phenotype in CTP: Phosphoethanolamine Cytidylyltransferase-deficient Mice
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DOI：
10.1074/jbc.m109.023846
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发表时间：
2009-09-18
影响因子：
4.8
通讯作者：
Bakovic, Marica
中科院分区：
文献类型：
--
作者：
Fullerton, Morgan D.;Hakimuddin, Fatima;Bakovic, Marica
磷脂酰乙醇胺（PE）是一种重要的内膜磷脂，主要通过PE-Kennedy途径和磷脂酰丝氨酸脱羧从头合成。CTP：磷酸乙醇胺胞苷酰转移酶（Pcyt 2）催化CDP-乙醇胺的形成，这通常是PE-Kennedy途径中的速率调节步骤。在目前的研究中，我们表明，减少CDP-乙醇胺形成Pcyt 2（+/-）小鼠限制了PE的合成速率，并增加了二酰基甘油的可用性。这导致甘油三酯的形成增加，这通过刺激从头脂肪酸合成和增加预先存在的脂肪酸的摄取来促进。Pcyt 2（+/-）小鼠随着年龄的增长逐渐积累更多的甘油二酯和甘油三酯，并具有改变的脂肪酸组成，主要是PE和甘油三酯。此外，Pcyt 2（+/-）在作为能量底物的脂肪酸利用中具有固有的阻断，并且在老年时对葡萄糖和胰岛素的耐受性受损。因此，基因表达分析表明主要的脂肪生成基因的上调和线粒体脂肪酸β-氧化基因的下调。这些数据首次表明，为了保护膜PE磷脂，Pcyt 2缺乏会产生甘油三酯和能量底物代谢的代偿性变化，导致肝脏脂肪变性、高甘油三酯血症、肥胖和胰岛素抵抗的进行性发展，这些是代谢综合征的主要特征。
Phosphatidylethanolamine (PE) is an important inner membrane phospholipid mostly synthesized de novo via the PE-Kennedy pathway and by the decarboxylation of phosphatidylserine. CTP:phosphoethanolamine cytidylyltransferase (Pcyt2) catalyzes the formation of CDP-ethanolamine, which is often the rate regulatory step in the PE-Kennedy pathway. In the current investigation, we show that the reduced CDP-ethanolamine formation in Pcyt2(+/-) mice limits the rate of PE synthesis and increases the availability of diacylglycerol. This results in the increased formation of triglycerides, which is facilitated by stimulated de novo fatty acid synthesis and increased uptake of pre-existing fatty acids. Pcyt2(+/-) mice progressively accumulate more diacylglycerol and triglycerides with age and have modified fatty acid composition, predominantly in PE and triglycerides. Pcyt2(+/-) additionally have an inherent blockage in fatty acid utilization as energy substrate and develop impaired tolerance to glucose and insulin at an older age. Accordingly, gene expression analyses demonstrated the up-regulation of the main lipogenic genes and down-regulation of mitochondrial fatty acid beta-oxidation genes. These data demonstrate for the first time that to preserve membrane PE phospholipids, Pcyt2 deficiency generates compensatory changes in triglyceride and energy substrate metabolism, resulting in a progressive development of liver steatosis, hypertriglyceridemia, obesity, and insulin resistance, the main features of the metabolic syndrome.