Spiegel S, Merrill A H
Department of Biochemistry and Molecular Biology, Georgetown University Medical Center, Washington, D.C. 20007, USA.
FASEB J. 1996 Oct;10(12):1388-97. doi: 10.1096/fasebj.10.12.8903509.
Sphingolipids have been implicated in the regulation of cell growth, differentiation, and programmed cell death. The current paradigm for their action is that complex sphingolipids such as gangliosides interact with growth factor receptors, the extracellular matrix, and neighboring cells, whereas the backbones--sphingosine and other long-chain or "sphingoid" bases, ceramides, and sphingosine 1-phosphate--activate or inhibit protein kinases and phosphatases, ion transporters, and other regulatory machinery. Tumor necrosis factor-alpha, interleukin 1beta, and nerve growth factor, for example, induce sphingomyelin hydrolysis to ceramide. Other agonists, such as platelet-derived growth factor, trigger further hydrolysis of ceramide to sphingosine and activate sphingosine kinase to form sphingosine 1-phosphate. These metabolites either stimulate or inhibit growth and may be cytotoxic (in some cases via induction of apoptosis), depending on which products are formed (or added exogenously), the cellular levels (and possibly intracellular localization), and the cell type. In Swiss 3T3 cells, for example, sphingosine and sphingosine 1-phosphate are growth stimulatory at low concentrations via calcium mobilization from intracellular stores and activation of the mitogen-activated protein kinase (MAP kinase) pathway and transcription factors (AP-1), but are toxic at high concentrations. High levels of endogenous sphingoid bases are also produced by inhibition of ceramide synthase by fumonisins, mycotoxins produced by Fusarium moniliforme, resulting in growth stimulation or toxicity. Thus, sphingolipid metabolites appear to serve as second messengers for growth factors, cytokines, and other "physiological" agonists and, when elevated abnormally, to lead to disease.
鞘脂类物质与细胞生长、分化及程序性细胞死亡的调节有关。目前关于其作用的范例是，诸如神经节苷脂等复杂鞘脂类物质与生长因子受体、细胞外基质及相邻细胞相互作用，而其骨架——鞘氨醇及其他长链或“鞘脂样”碱基、神经酰胺和1 -磷酸鞘氨醇——则激活或抑制蛋白激酶、磷酸酶、离子转运体及其他调节机制。例如，肿瘤坏死因子-α、白细胞介素1β和神经生长因子可诱导鞘磷脂水解生成神经酰胺。其他激动剂，如血小板衍生生长因子，可触发神经酰胺进一步水解为鞘氨醇，并激活鞘氨醇激酶形成1 -磷酸鞘氨醇。这些代谢产物可刺激或抑制生长，并且可能具有细胞毒性（在某些情况下通过诱导凋亡），这取决于生成的（或外源添加的）产物种类、细胞水平（以及可能的细胞内定位）和细胞类型。例如，在瑞士3T3细胞中，鞘氨醇和1 -磷酸鞘氨醇在低浓度时通过从细胞内储存库动员钙并激活丝裂原活化蛋白激酶（MAP激酶）途径和转录因子（AP - 1）来刺激生长，但在高浓度时具有毒性。伏马菌素（由串珠镰刀菌产生的霉菌毒素）抑制神经酰胺合酶也会产生高水平的内源性鞘脂样碱基，从而导致生长刺激或毒性。因此，鞘脂类代谢产物似乎充当生长因子、细胞因子及其他“生理性”激动剂的第二信使，当异常升高时会导致疾病。
