Sphingosine-1-phosphate (S1P) is not only a catabolic intermediate of all sphingolipids but also an evolutionary conserved bioactive lipid with critical functions in cell survival, differentiation, and migration as well as in immunity and angiogenesis. S1P-lyase (SGPL1) irreversibly cleaves S1P in the final step of sphingolipid catabolism. As sphingoid bases and their 1-phosphates are not only metabolic intermediates but also highly bioactive lipids that modulate a wide range of physiological processes, it would be predicted that their elevation might induce adjustments in other facets of sphingolipid metabolism and/or alter cell behavior. We actually found in a previous study that in terminally differentiated neurons SGPL1 deficiency increases sphingolipid formation via recycling at the expense of de novo synthesis. We now investigated whether and how SGPL1 deficiency affects the metabolism of (glyco)sphingolipids in mouse embryonic fibroblasts (MEFs). According to our previous experiments in neurons, we found a strong accumulation of S1P in SGPL1-deficient MEFs. Surprisingly, a completely different situation arose as we analyzed sphingolipid metabolism in this non-differentiated cell type. The production of biosynthetic precursors of complex glycosphingolipids including ceramide, glucosylceramide and also ganglioside GM3 via de novo synthesis and recycling pathway was substantially increased whereas the amount of more complex gangliosides dropped significantly.

中文翻译：

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S1P-裂解酶缺乏解耦神经节苷脂形成-对致瘤能力的潜在贡献。

鞘氨醇-1-磷酸酯（S1P）不仅是所有鞘脂的分解代谢中间体，还是进化上保守的生物活性脂质，在细胞存活，分化和迁移以及免疫和血管生成中具有关键功能。S1P裂解酶（SGPL1）在鞘脂分解代谢的最后一步不可逆地裂解S1P。由于鞘氨醇碱基及其1-磷酸不仅是代谢中间体，而且还是调节多种生理过程的高生物活性脂质，因此可以预见，它们的升高可能会引起鞘脂代谢其他方面的调节和/或改变细胞行为。我们实际上在先前的研究中发现，在终末分化神经元中SGPL1缺乏会通过循环而增加鞘脂形成，而从头合成的代价却是不足。现在，我们研究了SGPL1缺乏是否以及如何影响小鼠胚胎成纤维细胞（MEF）中（糖）鞘脂的代谢。根据我们先前在神经元中的实验，我们在SGPL1缺失的MEF中发现了S1P的大量积累。出乎意料的是，当我们分析这种未分化细胞类型中的鞘脂代谢时，出现了完全不同的情况。通过从头合成和再循环途径，复杂糖鞘脂的生物合成前体包括神经酰胺，葡萄糖基神经酰胺以及神经节苷脂GM3的产量大大增加，而更复杂的神经节苷脂的量则显着下降。我们发现SGPL1缺失的MEF中有大量的S1P积累。出乎意料的是，当我们分析这种未分化细胞类型中的鞘脂代谢时，出现了完全不同的情况。通过从头合成和再循环途径，复杂糖鞘脂的生物合成前体包括神经酰胺，葡萄糖基神经酰胺以及神经节苷脂GM3的产量大大增加，而更复杂的神经节苷脂的量则显着下降。我们发现SGPL1缺失的MEF中有大量的S1P积累。出乎意料的是，当我们分析这种未分化细胞类型中的鞘脂代谢时，出现了完全不同的情况。通过从头合成和再循环途径，复杂糖鞘脂的生物合成前体包括神经酰胺，葡萄糖基神经酰胺以及神经节苷脂GM3的产量大大增加，而更复杂的神经节苷脂的量则显着下降。