Sphingosine 1-Phosphate (S1P) Lyase Deficiency Increases Sphingolipid Formation via Recycling at the Expense of de Novo Biosynthesis in Neurons
Sphingosine 1-Phosphate (S1P) Lyase Deficiency Increases Sphingolipid Formation via Recycling at the Expense of de Novo Biosynthesis in Neurons
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DOI：
10.1074/jbc.m111.302380
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发表时间：
2012-03-16
影响因子：
4.8
通讯作者：
van Echten-Deckert, Gerhild
中科院分区：
文献类型：
--
作者：
Hagen-Euteneuer, Nadine;Luetjohann, Dieter;van Echten-Deckert, Gerhild
鞘脂1-磷酸裂解酶（S1P裂解酶）在鞘脂代谢的最后一步不可逆地裂解鞘脂1-磷酸（S1P）。由于鞘脂碱及其1-磷酸不仅是代谢中间体，而且是调节广泛生理过程的高生物活性脂质，因此可以预测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。事实上，我们以前曾报道过S1P裂解酶缺乏会导致神经退行性变和其他不良症状。接下来，我们提出了S1P裂解酶缺乏是否以及如何影响鞘脂和胆固醇的代谢的问题，这两种脂类可能参与了在S1P裂解酶缺乏小鼠中观察到的神经退行性过程。正如预测的那样，在消除S1P裂解酶后，游离和磷酸化的鞘脂基显著增加，但令我们惊讶的是，鞘脂（糖）的质量非但没有增加，反而保持在野生型水平。研究发现，这是由于新生括约肌碱生物合成减少以及通过打捞途径的脊柱再循环相应增加所致。尽管游离胆固醇维持在野生型水平，但胆固醇酯也有相当大的增加，这可能是鞘脂代谢变化的继发因素。总而言之，这些发现表明，由于S1P裂解酶的丧失，游离和磷酸化的鞘碱的积累导致了新生生物合成和再循环之间平衡的有趣调整，以维持（糖）鞘脂稳态。这些变化及其对其他细胞脂质代谢的影响，应该作为S1P裂解酶缺乏症神经退行性变的可能因素加以探讨。
Sphingosine 1-phosphate lyase (S1P lyase) irreversibly cleaves sphingosine 1-phosphate (S1P) in the final step of sphingolipid catabolism. As sphingoid bases and their 1-phosphate 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. Indeed, we have previously reported that S1P lyase deficiency causes neurodegeneration and other adverse symptoms. We next asked the question whether and how S1P lyase deficiency affects the metabolism of (glyco)sphingolipids and cholesterol, two lipid classes that might be involved in the neurodegenerative processes observed in S1P lyase-deficient mice. As predicted, there was a considerable increase in free and phosphorylated sphingoid bases upon elimination of S1P lyase, but to our surprise, rather than increasing, the mass of (glyco) sphingolipids persisted at wild type levels. This was discovered to be due to reduced de novo sphingoid base biosynthesis and a corresponding increase in the recycling of the backbones via the salvage pathway. There was also a considerable increase in cholesterol esters, although free cholesterol persisted at wild type levels, which might be secondary to the shifts in sphingolipid metabolism. All in all, these findings show that accumulation of free and phosphorylated sphingoid bases by loss of S1P lyase causes an interesting readjustment of the balance between de novo biosynthesis and recycling to maintain (glyco) sphingolipid homeostasis. These changes, and their impact on the metabolism of other cellular lipids, should be explored as possible contributors to the neurodegeneration in S1P lyase deficiency.