Genetics of Development and Disease Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Biol Chem. 2010 Apr 2;285(14):10880-9. doi: 10.1074/jbc.M109.081489. Epub 2010 Jan 24.
The cleavage of sphingoid base phosphates by sphingosine-1-phosphate (S1P) lyase to produce phosphoethanolamine and a fatty aldehyde is the final degradative step in the sphingolipid metabolic pathway. We have studied mice with an inactive S1P lyase gene and have found that, in addition to the expected increase of sphingoid base phosphates, other sphingolipids (including sphingosine, ceramide, and sphingomyelin) were substantially elevated in the serum and/or liver of these mice. This latter increase is consistent with a reutilization of the sphingosine backbone for sphingolipid synthesis due to its inability to exit the sphingolipid metabolic pathway. Furthermore, the S1P lyase deficiency resulted in changes in the levels of serum and liver lipids not directly within the sphingolipid pathway, including phospholipids, triacyglycerol, diacylglycerol, and cholesterol. Even though lipids in serum and lipid storage were elevated in liver, adiposity was reduced in the S1P lyase-deficient mice. Microarray analysis of lipid metabolism genes in liver showed that the S1P lyase deficiency caused widespread changes in their expression pattern, with a significant increase in the expression of PPARgamma, a master transcriptional regulator of lipid metabolism. However, the mRNA expression of the genes encoding the sphingosine kinases and S1P phosphatases, which directly control the levels of S1P, were not significantly changed in liver of the S1P lyase-deficient mice. These results demonstrate that S1P lyase is a key regulator of the levels of multiple sphingolipid substrates and reveal functional links between the sphingolipid metabolic pathway and other lipid metabolic pathways that may be mediated by shared lipid substrates and changes in gene expression programs. The disturbance of lipid homeostasis by altered sphingolipid levels may be relevant to metabolic diseases.
鞘氨醇磷酸酯由鞘氨醇-1-磷酸（S1P）裂合酶裂解生成磷酸乙醇胺和脂肪酸醛，是鞘脂代谢途径的最终降解步骤。我们研究了 S1P 裂合酶基因失活的小鼠，发现除了预期的鞘氨醇碱基磷酸增加外，这些小鼠的血清和/或肝脏中的其他鞘脂（包括鞘氨醇、神经酰胺和神经鞘磷脂）也显著升高。这种增加与鞘氨醇骨架因无法离开鞘脂代谢途径而重新用于鞘脂合成一致。此外，S1P 裂合酶缺乏导致血清和肝脏脂质水平发生变化，这些脂质不直接位于鞘脂途径内，包括磷脂、三酰甘油、二酰甘油和胆固醇。尽管血清和肝脏脂质储存中的脂质升高，但 S1P 裂合酶缺陷小鼠的肥胖程度降低。肝脏中脂质代谢基因的微阵列分析显示，S1P 裂合酶缺乏导致其表达模式广泛变化，脂质代谢的主要转录调节因子 PPARγ的表达显著增加。然而，S1P 裂合酶缺陷小鼠肝脏中编码鞘氨醇激酶和 S1P 磷酸酶的基因的 mRNA 表达没有显著变化，这些基因直接控制 S1P 的水平。这些结果表明 S1P 裂合酶是多种鞘脂底物水平的关键调节剂，并揭示了鞘脂代谢途径与其他脂质代谢途径之间的功能联系，这种联系可能通过共享脂质底物和基因表达程序的变化来介导。改变的鞘脂水平引起的脂质动态平衡紊乱可能与代谢疾病有关。
