Critical role of ABCA1 transporter in sphingosine 1‐phosphate release from astrocytes

Abstract

Sphingosine 1-phosphate (S1P) is accumulated in lipoproteins, especially high-density lipoprotein (HDL), in plasma. However, it remains uncharacterized how extracellular S1P is produced in the CNS. The treatment of rat astrocytes with retinoic acid and dibutyryl cAMP, which induce apolipoprotein E (apoE) synthesis and HDL-like lipoprotein formation, stimulated extracellular S1P accumulation in the presence of its precursor sphingosine. The released S1P was present together with apoE particles in the HDL fraction. S1P release from astrocytes was inhibited by the treatment of the cells with glybenclamide or small interfering RNAs specific to ATPbinding cassette transporter A1 (ABCA1). Astrocytes from Abca1)/) mice also showed impairment of retinoic acid/dibutyryl cAMP-induced S1P release in association with the blockage of HDL-like lipoprotein formation. However, the formation of either apoE or lipoprotein itself was not sufficient, and additional up-regulation of ABCA1 was requisite to stimulate S1P release. We conclude that the S1P release from astrocytes is coupled with lipoprotein formation through ABCA1. Keywords: apolipoprotein E, astrocyte, ATP-binding cassette transporter A1, high-density lipoprotein, sphingosine 1-phosphate. Sphingosine 1-phosphate (S1P), a sphingolipid metabolite, is a pleiotropic lipid mediator involved in a variety of cell activities, including morphology, motility, and growth. Five subtypes of S1P-specific receptors, S1P 1-5 , have been isolated so far (Ishii et al. 2004). In neural cells, these receptors are expressed in a cell-specific manner (Van Brocklyn et al. 1999;Sato et al. 2000) and involved in the regulation of neural cell functions; for example, a rapid process retraction through S1P 5 in oligodendrocytes (Jaillard et al. 2005), rounding of the cell body in PC12 and N1E115 cells (Postma et al. 1996;Sato et al. 1997) possibly through S1P 2 (Van Brocklyn et al. 1999), and regulation of motility in astrocytes and glioma cells . In addition, S1P induces the proliferation in astroglial cells, which was associated with the activation of extracellular signal-regulated kinase (ERK), activation of the phospholipase C, and Ca 2+ mobilization (Tas and Koschel 1998;Sato et al. 1999;Pebay et al. 2001). S1P 1 is more important than S1P 2 for the stimulation of ERK, while S1P 2 may be responsible for the activation of phospholipase C and Ca 2+ mobilization (Sato et al. 2000;Malchinkhuu et al. 2003). Thus, S1P and its receptors may play important roles in maintaining the functions of the CNS.We have recently demonstrated that S1P is concentrated in lipoproteins, such as high-density lipoprotein (HDL), in circulating blood (Murata et al. 2000b), and that the lipid mediates lipoprotein-induced anti-atherogenic actions, including cell survival, cell migration, and inhibition of adhesion molecule expression through S1P receptors in endothelial cells Okajima 2002). Thus, lipoproteins seem to serve as carriers for extracellular S1P in circulating blood. In astrocytes as well, plasma HDL ...

Estradiol Induces Export of Sphingosine 1-Phosphate from Breast Cancer Cells via ABCC1 and ABCG2

“…Studies from several laboratories, including ours, have suggested the involvement of ABC transporters in S1P export from mast cells (32), platelets (33), endothelial cells (34), astrocytes (35), thyroid follicular cell (45), fibroblasts (46), and erythrocytes (47). Similarly, using pharmacological and molecular approaches, we demonstrated that ABCC1 and ABCG2 are involved in E 2 -mediated transport of S1P and dihydro-S1P out of MCF-7 cells.…”

“…ABCC1 and ABCG2 Mediate E 2 -induced Export of S1P-Recent studies suggest that members of the ABC transporter family might be involved in release of S1P from several types of cells (32)(33)(34)(35). Three ABC transporters, ABCB1 (also known as multidrug resistant gene 1 (MDR1)) or p-glycoprotein, ABCC1 (also known as multidrug resistance protein 1 (MRP1)), and ABCG2 (also known as breast cancer resistance protein), appear to account for 80 -90% of multidrug-resistant human tumor cells (36).…”

Targeting the Metabolism and Receptors of Sphingosine-1- Phosphate for the Treatment of Rheumatoid Arthritis

“…Mitra et al (2006) revealed that the release of S1P from mast cells is regulated by ABCC1. Similarly, the ABCA1 transporter is critical for the release of S1P from astrocytes (Sato et al, 2007). In breast cancer the export of S1P mediated by ABCC1 and ABCG2 transporters is stimulated by estrogen receptor- (Takabe et al, 2010).…”

“…The mechanism by which S1P is exported from the inside to the outside of cells after synthesis is not fully understood. Several lines of evidence suggest the involvement of the ATP-binding cassette (ABC) family of transporters in S1P secretion (Kobayashi et al, 2006;Mitra et al, 2006;Sato et al, 2007). Mitra et al (2006) revealed that the release of S1P from mast cells is regulated by ABCC1.…”

The role of sphingosine-1-phosphate in the tumor microenvironment and its clinical implications

“…S1P export requires a carrier or transporter, and studies have suggested the involvement of ATP-binding cassette (ABC) transporters in this process from various types of cultured cells. 22 S1P is exported from mast cells via ABCC1 (also known as multidrug-resistant protein 1; MRP1), 32 from astrocytes via ABCA1, 33 from endothelial cells via ABCA1 and ABCC1, 34 and from thyroid carcinoma cells via ABCC1. 35 Furthermore, we demonstrated that ABCC1 and ABCG2 (also known as breast cancer resistance protein; BCRP) are involved in estradiol-mediated transport of S1P and dihydro-S1P out of MCF-7 human breast cancer cells.…”