Studies on neuronal functions by modulators of glycosphingolipid synthesis

近年来，神经节苷脂合成酶基因的克隆以及神经节苷脂生物合成抑制剂（D-P β）和促进剂（L-P β）的开发为神经节苷脂的生理功能研究开辟了新的方向。基于这些显著的进展，我们可以在这里证明：1）L-PdR在神经元细胞中的抗凋亡作用可能是该神经酰胺类似物与电压依赖性阴离子通道（VDAC）蛋白的特异性结合能力。由于VDAC定位于线粒体外膜并调节细胞色素C（通过线粒体的凋亡执行者）的释放，因此进一步研究L-PdR抑制VDAC功能的机制将为抗凋亡治疗开辟新的策略。2）TNF-α诱导脂肪细胞胰岛素抵抗状态的获得可能依赖于通过上调GM 3合成酶基因表达而增加GM 3生物合成。通过D-β-D-葡聚糖药理学耗竭脂肪细胞中的GM 3可防止TNF-α诱导的胰岛素依赖性信号传导缺陷。TNF增加细胞GM 3的合成可能参与了2型糖尿病胰岛素抵抗的病理过程。

Recent achievement on the molecular cloning of various ganglioside synthtase genes as well as the development of ganglioside biosynthesis inhibitor (D-PDMP) and accelerator (L-PDMP) leads us the new dimension for the elucidation of the physiological function of gangliosides. Based on these remarkable progress, we could demonstrate here that 1 ) The anti-apoptotic action of L-PDMP in neuronal cells may be the specific binding ability of this ceramide analog to voltage-dependent anion channel (VDAC) protein. Since VDAC localizes the mitochondrial outer membrane and regulates the release of cytochrome C (an executor of apoptosis through mitochondria), further study to elucidate the inhibitory mechanism of VDAC function by L-PDMP will open a new strategy for anti-apoptotic therapy. ; 2) Acquisition of a state of insulin resistance in adipocytes induced by TNF-α may depend upon increased GM3 biosynthesis through upregulation of GM3 synthase gene expression. Pharmacological depletion of GM3 in adipocytes by D-PDMP prevented the TNF-α-induced defect in insulin-dependent signaling. The increased synthesis of cellular GM3 by TNF may participate in the pathological conditions of insulin resistance in type 2 diabetes.