The therapeutic potential of modulating the ceramide/sphingomyelin pathway.
The therapeutic potential of modulating the ceramide/sphingomyelin pathway.
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DOI：
10.1172/jci16127
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发表时间：
2002-07
期刊：
影响因子：
--
通讯作者：
R. Kolesnick
中科院分区：
文献类型：
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作者：
R. Kolesnick
鞘脂类的膜脂质含有长链鞘氨醇碱骨架（如鞘氨醇）、酰胺连接的长链脂肪酸和各种极性头部基团之一。这些头部基团的结构定义了各种鞘脂亚型，神经酰胺中有羟基，鞘磷脂（SM）中有磷酸胆碱，鞘糖脂中有碳水化合物（图11，未显示）。由于SM集中在质膜的外叶中，并为细胞外环境提供屏障（1），因此长期以来一直认为它仅起结构作用。然而，在1987年，我们的实验室首次报道了响应于1，2-二酰基甘油而不是佛波醇酯的快速鞘磷脂酶（SMase）激活（2），并提出了基于SM的信号传导途径的存在（3，4）。随后，Hannun及其同事表明，该途径可以通过受体介导的机制激活（5），并提供了神经酰胺是第二信使的证据（6）。事实上，鞘脂代谢已被证明是一个动态过程，鞘脂代谢物-包括神经酰胺，鞘氨醇和鞘氨醇1-磷酸（S1 P）-现在被认为是信使在细胞生长，存活和死亡中发挥重要作用（7，8）。图1鞘脂中间体代谢示意图。
Membrane lipids of the sphingolipid class contain a long-chain sphingoid base backbone (such as sphingosine), an amide-linked, long-chain fatty acid, and one of various polar head groups. The structure of these head groups defines the various sphingolipid subtypes, with a hydroxyl group found in ceramide, phosphorylcholine in sphingomyelin (SM), and carbohydrates in glycosphingolipids (Figure (Figure11 and not shown). Because SM is concentrated in the outer leaflet of the plasma membrane and provides a barrier to the extracellular environment (1), it was long assumed to serve only structural roles. However, in 1987 our laboratory reported for the first time rapid sphingomyelinase (SMase) activation in response to 1,2-diacylglycerols but not phorbol esters (2), and proposed the existence of an SM-based signaling pathway (3, 4). Subsequently, Hannun and coworkers showed that this pathway can be activated by receptor-mediated mechanisms (5) and provided evidence that ceramide is a second messenger (6). Indeed, sphingolipid metabolism has proved to be a dynamic process, and sphingolipid metabolites — including ceramide, sphingosine, and sphingosine 1-phosphate (S1P) — are now recognized as messengers playing essential roles in cell growth, survival, and death (7, 8). Figure 1 Schematic representation of sphingolipid intermediary metabolism.