Studies on neuronal functions by modulators of glycosphingolipid synthesis

近年来，神经节苷脂合成酶基因的分子克隆以及神经节苷脂生物合成抑制剂(D-PDMP)和促进剂(L-PDMP)的发展为阐明神经节苷脂的生理功能提供了新的维度。基于这些显著的进展，我们可以在这里证明：1)L的抗神经细胞凋亡作用可能是这种神经酰胺类似物与电压依赖性阴离子通道蛋白的特异结合能力。由于VDAC定位于线粒体外膜并调节细胞色素C的释放(细胞色素C通过线粒体执行细胞)，进一步研究L-PDMP抑制VDAC功能的机制将为抗细胞凋亡治疗开辟新的策略。2)肿瘤坏死因子-α诱导的脂肪细胞胰岛素抵抗状态的形成可能依赖于通过上调GM3合成酶基因的表达而增加GM3的生物合成。药物耗竭脂肪细胞中的GM3可阻止肿瘤坏死因子-α诱导的胰岛素依赖信号转导缺陷。肿瘤坏死因子促进细胞GM3合成可能参与了2型糖尿病胰岛素抵抗的病理状态。

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.