Brindley D N, Abousalham A, Kikuchi Y, Wang C N, Waggoner D W
Signal Transduction Laboratories, Faculty of Medicine, University of Alberta, Edmonton, Canada.
Biochem Cell Biol. 1996;74(4):469-76. doi: 10.1139/o96-051.
Hydrolysis of phosphatidylcholine via receptor-mediated stimulation of phospholipase D produces phosphatidate that can be converted to lysophosphatidate and diacylglycerol. Diacylglycerol is an activator of protein kinase C, whereas phosphatidate and lysophosphatidate stimulate tyrosine kinases and activate the Ras-Raf-mitogen-activated protein kinase pathway. These three lipids can stimulate cell division. Conversely, activation of sphingomyelinase by agonists (e.g., tumor necrosis factor-alpha) causes ceramide production that inhibits cell division and produces apoptosis. If ceramides are metabolized to sphingosine and sphingosine 1-phosphate, then these lipids can stimulate phospholipase D and are also mitogenic. By contrast, ceramides inhibit the activation of phospholipase D by decreasing its interaction with the G-proteins, ARF and Rho, which are necessary for its activation. In whole cells, ceramides also stimulate the degradation of phosphatidate, lysophosphatidate, ceramide 1-phosphate, and sphingosine 1-phosphate through a multifunctional phosphohydrolase (the Mg(2+)-independent phosphatidate phosphohydrolase), whereas sphingosine inhibits phosphatidate phosphohydrolase. Tumor necrosis factor-alpha causes insulin resistance, which may be partly explained by ceramide production. Cell-permeable ceramides decrease insulin-stimulated glucose uptake in 3T3-L1 adipocytes after 2-24 h, whereas they stimulate basal glucose uptake. These effects do not depend on decreased tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1 or the interaction of insulin receptor substrate-1 with phosphatidylinositol 3-kinase. They appear to rely on the differential effects of ceramides on the translocation of GLUT1-and GLUT4-containing vesicles. It is concluded that there is a significant interaction and "cross-talk" between the sphingolipid and glycerolipid pathways that modifies signal transduction to control vesicle movement, cell division, and cell death.
通过受体介导的磷脂酶D刺激作用使磷脂酰胆碱水解，产生磷脂酸，磷脂酸可转化为溶血磷脂酸和二酰基甘油。二酰基甘油是蛋白激酶C的激活剂，而磷脂酸和溶血磷脂酸则刺激酪氨酸激酶并激活Ras-Raf-丝裂原活化蛋白激酶途径。这三种脂质均可刺激细胞分裂。相反，激动剂（如肿瘤坏死因子-α）激活鞘磷脂酶会导致神经酰胺生成，从而抑制细胞分裂并引发细胞凋亡。如果神经酰胺代谢为鞘氨醇和1-磷酸鞘氨醇，那么这些脂质可刺激磷脂酶D，并且也具有促有丝分裂作用。相比之下，神经酰胺通过减少与G蛋白、ARF和Rho的相互作用来抑制磷脂酶D的激活，而这些蛋白对于磷脂酶D的激活是必需的。在完整细胞中，神经酰胺还通过一种多功能磷酸水解酶（不依赖Mg(2+)的磷脂酸磷酸水解酶）刺激磷脂酸、溶血磷脂酸、1-磷酸神经酰胺和1-磷酸鞘氨醇的降解，而鞘氨醇则抑制磷脂酸磷酸水解酶。肿瘤坏死因子-α会导致胰岛素抵抗，这可能部分归因于神经酰胺的生成。可透过细胞的神经酰胺在2至24小时后会降低3T3-L1脂肪细胞中胰岛素刺激的葡萄糖摄取，而它们会刺激基础葡萄糖摄取。这些作用并不依赖于胰岛素受体和胰岛素受体底物-1酪氨酸磷酸化的降低，也不依赖于胰岛素受体底物-1与磷脂酰肌醇3-激酶的相互作用。它们似乎依赖于神经酰胺对含GLUT1和GLUT4囊泡转运的不同影响。得出的结论是，鞘脂和甘油脂途径之间存在显著的相互作用和“串扰”，这种相互作用会改变信号转导，从而控制囊泡运动、细胞分裂和细胞死亡。
