Triacylglycerol/phospholipid molecular species profiling of fatty livers and regenerated non-fatty livers in cystathionine beta-synthase-deficient mice, an animal model for homocysteinemia/homocystinuria
Triacylglycerol/phospholipid molecular species profiling of fatty livers and regenerated non-fatty livers in cystathionine beta-synthase-deficient mice, an animal model for homocysteinemia/homocystinuria
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DOI：
10.1007/s00216-011-4703-2
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发表时间：
2011-06-01
影响因子：
4.3
通讯作者：
Ishii, Isao
中科院分区：
文献类型：
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作者：
Ikeda, Kazutaka;Kubo, Akiko;Ishii, Isao
脂肪肝是同型半胱氨酸血症/同型半胱氨酸尿患者及其遗传动物模型——缺乏胱氨酸-合酶（Cbs(-/-)）小鼠的典型表现之一。绝大多数Cbs（-/-）在出生后4周内死亡，其机制尚不清楚，而一小部分存活到成年，在哺乳期通过再生避免肝脏脂肪变性。为了研究这种脂肪变化的分子基础，我们使用基于芯片的纳米esi（电喷雾电离）-质谱系统分析了2周龄Cbs（-/-）和8周龄Cbs（-/-）幸存者的脂肪肝中的脂质成分，该系统可以定量检测三酰基甘油/磷脂分子种类。在2周时，Cbs小鼠肝脏中所有主要三酰甘油种类的水平（-/-）都比野生型小鼠高得多，尽管在8周时没有。某些磷脂种类的水平在2周龄Cbs中出现上调或下调（-/-）；例如饱和脂肪酸（16:0和18:0）或单不饱和脂肪酸（16:1和18:1）含有磷脂酰胆碱/磷脂酰乙醇胺的种类上调，而含有磷脂酰胆碱（18:2-18:2和18:2-20:5）、磷脂酰乙醇胺（18:1-20:4）和磷脂酰肌醇（18:0-20:4）的多不饱和脂肪酸下调。毛细管电泳-质谱分析发现，2周龄Cbs的脂肪肝（-/-）中s-腺苷蛋氨酸和s-腺苷同型半胱氨酸积累水平较高，而8周龄Cbs的非脂肪肝（-/-）中s-腺苷蛋氨酸和s-腺苷同型半胱氨酸积累水平较低。尽管2周龄Cbs的肝脏s -腺苷蛋氨酸/ s -腺苷同型半胱氨酸比率（-/-）与野生型相当，但在Cbs的脂肪肝中，整体蛋白精氨酸甲基化受到干扰（-/-）。我们的研究结果提示，磷脂含量改变介导的细胞信号可能参与了Cbs（-/-）脂肪肝的发病机制。
Fatty liver is one of the typical manifestations in homocysteinemia/homocystinuria patients and their genetic animal model, mice lacking cystathionine beta-synthase (Cbs (-/-)). The vast majority of Cbs (-/-) die within 4 weeks after birth via yet unknown mechanisms, whereas a small portion survive to adulthood, escaping fatty degeneration of the liver during lactation periods, through regeneration. To investigate the molecular basis of such fatty changes, we analyzed lipid components in fatty livers of 2-week-old Cbs (-/-) and regenerated non-fatty livers of 8-week-old Cbs (-/-) survivors using a chip-based nanoESI (electrospray ionization)-MS system, which allows quantitative detection of triacylglycerol/phospholipid molecular species. Hepatic levels of all major triacylglycerol species were much higher in Cbs (-/-) than in wild-type mice at 2 weeks, although not at 8 weeks. Levels of some phospholipid species were either up- or downregulated in 2-week-old Cbs (-/-); e.g. saturated (16:0 and 18:0) or mono-unsaturated (16:1 and 18:1) fatty acids-containing phosphatidylcholine/phosphatidylethanolamine species were upregulated, while poly-unsaturated fatty acids-containing phosphatidylcholine (18:2-18:2 and 18:2-20:5), phosphatidylethanolamine (18:1-20:4), and phosphatidylinositol (18:0-20:4) were downregulated. Capillary electrophoresis-MS analysis identified high-level accumulation of S-adenosylmethionine and S-adenosylhomocysteine in fatty livers of 2-week-old Cbs (-/-) but much less in non-fatty livers of 8-week-old Cbs (-/-). Although hepatic S-adenosylmethionine/S-adenosylhomocysteine ratios were comparable between 2-week-old Cbs (-/-) and wild-type, global protein arginine methylation was disturbed in fatty livers of Cbs (-/-). Our results suggest that cellular signaling mediated by altered phospholipid contents might be involved in pathogenesis of fatty liver in Cbs (-/-).