Serine palmitoyl-CoA transferase (SPT) deficiency and sphingolipid levels in mice
Serine palmitoyl-CoA transferase (SPT) deficiency and sphingolipid levels in mice
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DOI：
10.1016/j.bbalip.2005.08.006
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发表时间：
2005-10-15
影响因子：
4.8
通讯作者：
Jiang, XC
中科院分区：
文献类型：
--
作者：
Hojjati, MR;Li, ZQ;Jiang, XC
鞘脂在细胞膜形成、信号转导和血浆脂蛋白代谢中起着非常重要的作用，所有这些功能都可能对动脉粥样硬化的发展产生影响。丝氨酸棕榈酰辅酶A转移酶（SPT）是鞘脂生物合成的关键酶。为了评估体内SPT活性及其在鞘脂代谢中的作用，我们将同源重组应用于胚胎干细胞，产生具有长链碱基1（Sptlc 1）和长链碱基2（Sptlc 2）的小鼠，这是SPT的两个亚基，基因缺陷，纯合Sptlc 11和Sptlc 2小鼠是胚胎致死的，而两种动物的杂合版本（Sptlc 1（+），Sptlc 2 *）是健康的。分析表明，与WT小鼠相比，Sptlc 1（+）（-）和Sptlc 2（+ -）小鼠具有：（1）肝脏Sptlc 1和Sptlc 2 mRNA降低44%和57%，（P < 0.01和P < 0.0001）;（2）使肝脏Sptlc 1质量减少50%，Sptlc 2质量减少70% Sptlc 2（+）（-）小鼠肝脏中Sptlc 1的质量减少了70%，而Sptlc 1（+）小鼠肝脏中Sptlc 2的质量减少了53（3）使肝脏SPT活性分别降低45%和60%（P < 0.01）;（4）肝脏神经酰胺减少（分别为22%和39%，P < 0.05和P < 0.01）和鞘氨醇水平（分别为22%和31%，P < 0.05和P < 0.01）;（5）血浆神经酰胺减少（分别为45%和39%，P < 0.01），鞘氨醇-1-磷酸（分别为31%和32%，P < 0.01）和鞘氨醇水平（分别为22.50%和25%，P < 0.01）;（6）显著降低血浆溶血鞘磷脂（分别为17倍和16倍，P < 0.0001），（7）血浆鞘磷脂、甘油三酯、总胆固醇、磷脂和肝鞘磷脂水平无变化。这些结果表明，Sptlc 1和Sptlc 2相互作用是体内SPT活性所必需的，并且SPT活性直接影响血浆鞘脂水平，此外，SPT活性的操纵可能很好地影响动脉粥样硬化等疾病的进程。(c)2005 Elsevier B. V.保留所有权利。
Sphingolipids play a very important role in cell membrane formation, signal transduction, and plasma lipoprotein metabolism, and all these functions may have an impact on atherosclerotic development. Serine palmitoyl-CoA transferase (SPT) is the key enzyme in sphingolipid biosynthesis. To evaluate in vivo SPT activity and its role in sphingolipid metabolism, we applied homologous recombination to embryonic stem cells, producing mice with long chain base 1 (Sptlc1) and long chain base 2 (Sptlc2), two subunits of SPT, gene deficiency, Homozygous Sptlc11 and Sptlc2 mice are embryonic lethal, whereas heterozygous versions of both animals (Sptlc1 (+), Sptlc2*) are healthy. Analysis showed that, compared with WT mice, Sptlc1 (+) (-) and Sptlc 2 (+ -) mice had: (1) decreased liver Sptlc1 and Sptlc2 mRNA by 44%, and 57% (P < 0.01 and P < 0.0001, respectively); (2) decreased liver Sptlc1 mass by 50% and Sptlc2 mass by 70% (P < 0.01 and P < 0.01, respectively), moreover, Sptlc1 mass decreased by 70% in Sptlc2 (+) (-) mouse liver, while Sptlc2 mass decreased by 53% in Sptlc 1 (+) mouse liver (P < 0.001 and P < 0.01, respectively); (3) decreased liver SPT activity by 45% and 60% (P < 0.01, respectively); (4)decreased liver ceramide (22% and 39%, P < 0.05 and P < 0.01, respectively) and sphingosine levels (22% and 31%, P < 0.05 and P < 0.01, respectively); (5) decreased plasma ceramide (45% and 39%, P < 0.01, respectively), sphingosine-1-phosphate (31% and 32%, P < 0.01, respectively) and sphingosine levels (22.50% and 25%, P < 0.01, respectively); (6) dramatically decreased plasma lysosphingomyelin (17-fold and 16-fold, P < 0.0001, respectively), and (7) no change of plasma sphingomyelin, triglyceride, total cholesterol, phospholipids, and liver sphingomyelin levels. These results indicated that both Sptlc1 and Sptlc2 interactions are necessary for SPT activity in vivo, and that SPT activity directly influences plasma sphingolipid levels, Furthermore, manipulation of SPT activity might well influence the course of such diseases as atherosclerosis. (c) 2005 Elsevier B.V. All rights reserved.