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. 2013 Jan;1831(1):193-202.
doi: 10.1016/j.bbalip.2012.06.007. Epub 2012 Jun 23.

Shaping the Landscape: Metabolic Regulation of S1P Gradients

Free PMC article

Shaping the Landscape: Metabolic Regulation of S1P Gradients

Ana Olivera et al. Biochim Biophys Acta. .
Free PMC article


Sphingosine-1-phosphate (S1P) is a lipid that functions as a metabolic intermediate and a cellular signaling molecule. These roles are integrated when compartments with differing extracellular S1P concentrations are formed that serve to regulate functions within the immune and vascular systems, as well as during pathologic conditions. Gradients of S1P concentration are achieved by the organization of cells with specialized expression of S1P metabolic pathways within tissues. S1P concentration gradients underpin the ability of S1P signaling to regulate in vivo physiology. This review will discuss the mechanisms that are necessary for the formation and maintenance of S1P gradients, with the aim of understanding how a simple lipid controls complex physiology. This article is part of a Special Issue entitled Advances in Lysophospholipid Research.


FIGURE 1. Cellular S1P metabolism
Cellular synthesis and degradation of S1P involves multiple enzymes, some expressed as various isoforms with different biochemical properties and cellular locations, indicating a highly complex metabolism. S1P synthesis by Sphk1 and 2 can occur after the degradation of ceramide, which takes place in the ER and in the Golgi after de novo synthesis, or in the lysosomes and at the plasma membrane, during catabolism of sphingomyelin and glycosphingolipids. Sphk1 activity (bold) predominates at the plasma membrane, while Sphk2 activity (bold) predominates for ER associated S1P metabolism. Within the cell, S1P may move rapidly between cell compartments. Intracellular S1P can be degraded by S1P lyase, dephosphorylated by S1P phosphatases to recycle the sphingoid base for ceramide synthesis, or else secreted. S1P is transported outside the cell by members of the ABC family of transporters and by Spns2. Once in the extracellular space, S1P can be dephosphorylated by a group of lipid phosphatases, LPPs, liberating sphingosine, which can be rephosphorylated back to S1P. Sph, sphingosine; Cer, ceramide; ethanolamine-P, ethanolamine phosphate; SM, sphingomyelin; GSL, glycosphingolipids; Ser, serine; LPPs, lipid phosphatases; CerS, ceramide synthase; CDase, ceramidase; SMase, sphingomyelinase; PM, plasma membrane.
FIGURE 2. Cellular regulation of S1P gradients
S1P concentration is maintained at a high concentration in blood (~1 μM) mostly by red blood cells and endothelial cells. Whereas the active transport of S1P from red blood cells can occur via ABC-type transporters (grey ovals), endothelial cell-derived S1P is transported into the luminal side of blood vessels via Spns2 transporters (blue ovals). S1P in circulation is predominantly bound to HDL or albumin (extracellular S1P is depicted generically as orange circles indicating either carrier-bound S1P or free S1P). These carrier proteins in serum can also extract S1P directly from the red blood cell membrane in a transporter-independent manner. Endothelial cells face two distinct S1P environments (illustrated as a color gradient on the right side of the figure), one rich in S1P at the luminal side and one about two to three orders of magnitude lower at the abluminal side, and they are key cellular components contributing to this sharp concentration differential. S1P from blood enters the endothelial cells constantly after dephosphorylation by plasma membrane lipid phosphate phosphatases (six-transmembrane domain structures). The resultant sphingosine is converted to S1P mainly by SphK2 and routed for irreversible degradation by S1P lyase. Similarly, S1P lyase present in various types of parenchymal cells also degrades S1P that traverses the endothelial barrier. In addition to the general skewing toward S1P production at the luminal side and S1P degradation at the abluminal side of blood vessels, new findings indicate the presence of microgradients of S1P at the perivascular space in the thymus to facilitate the egress of mature thymocytes into circulation. These gradients are maintained by endothelial cells and pericytes, which produce S1P and export it into the abluminal side of vessels via Spns2 transporters, as well as reticular epithelial cells at the farthest end of the perivascular area, which dephosphorylate S1P via the lipid phosphate phosphatase LPP3. Thus, the concerted actions of all these cells using distinct metabolic enzymes and transporters result in a concentration gradient of S1P critical for the exit of mature T cells from thymus. Cer, ceramide; Sph, sphingosine; EP, ethanolamine phosphate; HD hexadecenal; T, thymocyte; Per, pericyte; EpC, epithelial cell; RBC, red blood cell; EC, endothelial cell.

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