Abnormal lipid metabolism in cystathionine β-synthase-deficient mice, an animal model for hyperhomocysteinemia
Abnormal lipid metabolism in cystathionine β-synthase-deficient mice, an animal model for hyperhomocysteinemia
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DOI：
10.1074/jbc.m406820200
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发表时间：
2004-12-17
影响因子：
4.8
通讯作者：
Kimura, H
中科院分区：
文献类型：
--
作者：
Namekata, K;Enokido, Y;Kimura, H
高同型半胱氨酸血症(HHCY)是蛋氨酸/半胱氨酸代谢受损的结果，由缺乏维生素和/或酶，如胱硫氨酸β-合成酶(CBS)引起。虽然HHCY是心血管疾病的一个重要和独立的危险因素，这些疾病通常与肝脏脂肪变性有关，但同型半胱氨酸促进脂肪肝发展的机制尚不清楚。CBS缺陷(CBS-/-)小鼠以前是通过CBS基因的靶向缺失而产生的，表现出与HHCY患者相似的病理特征，包括内皮功能障碍和肝脏脂肪变性。在这里，我们显示了CBS-/-小鼠的脂代谢异常。CBS-/-小鼠肝脏和血清中甘油三酯和非酯化脂肪酸水平显著升高。在CBS-/-小鼠的肝脏中，脂肪酸β-氧化的关键酶--硫解酶的活性显著受损。CBS-/-小鼠肝脏载脂蛋白B100水平降低，而血清载脂蛋白B100和极低密度脂蛋白水平升高。CBS-/-小鼠血清高密度脂蛋白部分的胆固醇/磷脂水平降低，但总胆固醇/磷脂水平不降低，卵磷脂-胆固醇酰基转移酶活性严重受损。在CBS-/-小鼠血清中观察到异常的高密度脂蛋白颗粒，在聚丙烯酰胺凝胶电泳中具有较高的迁移率。此外，在CBS-/-小鼠中，血清胆固醇/甘油三酯在脂蛋白部分的分布发生了变化。这些结果表明，CBS-/-小鼠的肝脏脂肪变性是由脂代谢异常引起的或与之相关。
Hyperhomocysteinemia (HHCY) is a consequence of impaired methionine/cysteine metabolism and is caused by deficiency of vitamins and/or enzymes such as cystathionine beta-synthase (CBS). Although HHCY is an important and independent risk factor for cardiovascular diseases that are commonly associated with hepatic steatosis, the mechanism by which homocysteine promotes the development of fatty liver is poorly understood. CBS-deficient (CBS-/-) mice were previously generated by targeted deletion of the Cbs gene and exhibit pathological features similar to HHCY patients, including endothelial dysfunction and hepatic steatosis. Here we show abnormal lipid metabolism in CBS-/- mice. Triglyceride and nonesterified fatty acid levels were markedly elevated in CBS-/- mouse liver and serum. The activity of thiolase, a key enzyme in beta-oxidation of fatty acids, was significantly impaired in CBS-/- mouse liver. Hepatic apolipoprotein B100 levels were decreased, whereas serum apolipoprotein B100 and very low density lipoprotein levels were elevated in CBS-/- mice. Serum levels of cholesterol/phospholipid in high density lipoprotein fractions but not of total cholesterol/phospholipid were decreased, and the activity of lecithin-cholesterol acyltransferase was severely impaired in CBS-/- mice. Abnormal high density lipoprotein particles with higher mobility in polyacrylamide gel electrophoresis were observed in serum obtained from CBS-/- mice. Moreover, serum cholesterol/triglyceride distribution in lipoprotein fractions was altered in CBS-/- mice. These results suggest that hepatic steatosis in CBS-/- mice is caused by or associated with abnormal lipid metabolism.