Stearoyl-CoA desaturase 1 deficiency increases CTP:choline cytidylyltransferase translocation into the membrane and enhances phosphatidylcholine synthesis in liver
Stearoyl-CoA desaturase 1 deficiency increases CTP:choline cytidylyltransferase translocation into the membrane and enhances phosphatidylcholine synthesis in liver
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DOI：
10.1074/jbc.m502436200
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发表时间：
2005-06-17
影响因子：
4.8
通讯作者：
Ntambi, JM
中科院分区：
文献类型：
--
作者：
Dobrzyn, A;Dobrzyn, P;Ntambi, JM
硬脂酰辅酶A去饱和酶（SCD）是单不饱和脂肪酸合成中的限速酶。此前，我们发现 Scd1 缺乏会降低瘦小鼠和肥胖小鼠肝脏甘油三酯的积累，并显着降低极低密度脂蛋白的合成及其分泌。在本研究中，我们发现 Scd1 缺陷显着调节肝甘油磷脂谱。 Scd1-/-小鼠肝脏中磷脂酰胆碱（PC）含量增加40%，PC从头合成限速酶CTP：胆碱胞苷酰转移酶（CCT）和胆碱磷酸转移酶活性分别增加64%和53%。相比之下，Scd1-/-小鼠肝脏中磷脂酰乙醇胺N-甲基转移酶（一种通过磷脂酰乙醇胺甲基化参与PC合成的酶）的蛋白质水平降低了80%。 CCT 的激活需要膜易位。免疫印迹分析表明，与野生型小鼠相比，Scd1-/- 肝脏中与质膜相关的 CCT α 是野生型小鼠的两倍，表明 Scd1 突变导致 CCT 膜亲和力增加。与野生型小鼠相比，Scd1-/-原代肝细胞中[H-3]甘油掺入PC的量增加了2.5倍。此外，Scd1-/-小鼠肝脏中线粒体甘油-3-磷酸酰基转移酶活性降低了42%；然而，微粒体3-磷酸甘油酰基转移酶、二酰基甘油酰基转移酶和乙醇胺磷酸转移酶的活性不受Scd1突变的影响。我们的研究表明，SCD1 缺陷通过促进 CCT 易位到膜中而特异性地增加 CCT 活性，并增强肝脏中 PC 的生物合成。
Stearoyl-CoA desaturase (SCD) is the rate-limiting enzyme in monounsaturated fatty acid synthesis. Previously, we showed that Scd1 deficiency reduces liver triglyceride accumulation and considerably decreases synthesis of very low density lipoprotein and its secretion in both lean and obese mice. In the present study, we found that Scd1 deficiency significantly modulates hepatic glycerophospholipid profile. The content of phosphatidylcholine (PC) was increased by 40% and the activities of CTP:choline cytidylyltransferase (CCT), the rate-limiting enzyme in de novo PC synthesis, and choline phosphotransferase were increased by 64 and 53%, respectively, in liver of Scd1-/- mice. In contrast, the protein level of phosphatidylethanolamine N-methyltransferase, an enzyme involved in PC synthesis via methylation of phosphatidylethanolamine, was decreased by 80% in the liver of Scd1-/- mice. Membrane translocation of CCT is required for its activation. Immunoblot analyses demonstrated that twice as much CCT alpha was associated with plasma membrane in livers of Scd1-/- compared with wild type mice, suggesting that Scd1 mutation leads to an increase in CCT membrane affinity. The incorporation of [H-3] glycerol into PC was increased by 2.5-fold in Scd1-/- primary hepatocytes compared with those of wild type mice. Furthermore, mitochondrial glycerol-3-phosphate acyltransferase activity was reduced by 42% in liver of Scd1-/- mice; however, the activities of microsomal glycerol-3-phosphate acyltransferase, diacylglycerol acyltransferase, and ethanolamine phosphotransferase were not affected by Scd1 mutation. Our study revealed that SCD1 deficiency specifically increases CCT activity by promoting its translocation into membrane and enhances PC biosynthesis in liver.