Journal of Physiology and Biochemistry

, Volume 72, Issue 4, pp 657–667 | Cite as

ApoA-I induces S1P release from endothelial cells through ABCA1 and SR-BI in a positive feedback manner

  • Xing Liu
  • Kun Ren
  • Rong Suo
  • Sheng-Lin Xiong
  • Qing-Hai Zhang
  • Zhong-Cheng Mo
  • Zhen-Li Tang
  • Yue Jiang
  • Xiao-Shan Peng
  • Guang-Hui YiEmail author
Original Paper


Sphingosine-1-phosphate (S1P), which has emerged as a pivotal signaling mediator that participates in the regulation of multiple cellular processes, is derived from various cells, including vascular endothelial cells. S1P accumulates in lipoproteins, especially HDL, and the majority of free plasma S1P is bound to HDL. We hypothesized that HDL-associated S1P is released through mechanisms associated with the HDL maturation process. ApoA-I, a major HDL apolipoprotein, is a critical factor for nascent HDL formation and lipid trafficking via ABCA1. Moreover, apoA-I is capable of promoting bidirectional lipid movement through SR-BI. In the present study, we confirmed that apoA-I can facilitate the production and release of S1P by HUVECs. Furthermore, we demonstrated that ERK1/2 and SphK activation induced by apoA-I is involved in the release of S1P from HUVECs. Inhibitor and siRNA experiments showed that ABCA1 and SR-BI are required for S1P release and ERK1/2 phosphorylation induced by apoA-I. However, the effects triggered by apoA-I were not suppressed by inhibiting ABCA1/JAK2 or the SR-BI/Src pathway. S1P released due to apoA-I activation can stimulate the (ERK1/2)/SphK1 pathway through S1PR (S1P receptor) 1/3. These results indicated that apoA-I not only promotes S1P release through ABCA1 and SR-BI but also indirectly activates the (ERK1/2)/SphK1 pathway by releasing S1P to trigger their receptors. In conclusion, we suggest that release of S1P induced by apoA-I from endothelial cells through ABCA1 and SR-BI is a self-positive-feedback process: apoA-I-(ABCA1 and SR-BI)-(S1P release)-S1PR-ERK1/2-SphK1-(S1P production)-(more S1P release induced by apoA-I).


S1P SR-BI ABCA1 SphK S1P receptors Release 



ATP-binding cassette


Extracellular receptor kinase 1/2


Free cholesterol


Histone deacetylases


High-density lipoprotein


HDL-associated S1P


High-performance liquid chromatography


Human umbilical vein endothelial cells


Janus kinase 2






S1P receptor


Sphingosine kinase


Scavenger receptor class B type I


TNF receptor-associated factor 2



This work was sponsored by the National Natural Science Foundation of China (Nos. 81270360 and 31400652), Scientific Research Fund of Hunan Provincial Education Department (13C838), the Science and Technology Planning Project of Hunan Provincial Science and Technology Department (2014FJ2012), the Aid Program for Science and Technology Innovative Research Team in Higher Educational Institutions (2008-244) of Hunan Province, and the construct program of the key discipline in Hunan Province, China (Basic Medicine Sciences in University of South China, Xiangjiaofa No. [2011]76).


  1. 1.
    Alvarez SE, Harikumar KB, Hait NC et al (2010) Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2. Nature 465:1084–1088CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Anliker B, Chun J (2004) Lysophospholipid G protein-coupled receptors. J Biol Chem 279:20555–20558CrossRefPubMedGoogle Scholar
  3. 3.
    Barter P, Gotto AM, LaRosa JC et al (2007) HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med 357:1301–1310CrossRefPubMedGoogle Scholar
  4. 4.
    Catarzi S, Romagnoli C, Marcucci G, Favilli F, Iantomasi T, Vincenzini MT (2011) Redox regulation of ERK1/2 activation induced by sphingosine 1-phosphate in fibroblasts: involvement of NADPH oxidase and platelet-derived growth factor receptor. Biochim Biophys Acta 1810:446–456CrossRefPubMedGoogle Scholar
  5. 5.
    Duong PT, Collins HL, Nickel M, Lund-Katz S, Rothblat GH, Phillips MC (2006) Characterization of nascent HDL particles and microparticles formed by ABCA1-mediated efflux of cellular lipids to apoA-I. J Lipid Res 47:832–843CrossRefPubMedGoogle Scholar
  6. 6.
    Hait NC, Allegood J, Maceyka M et al (2009) Regulation of histone acetylation in the nucleus by sphingosine-1-phosphate. Science 325:1254–1257CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Hait NC, Oskeritzian CA, Paugh SW, Milstien S, Spiegel S (2006) Sphingosine kinases, sphingosine 1-phosphate, apoptosis and diseases. Biochim Biophys Acta 1758:2016–2026CrossRefPubMedGoogle Scholar
  8. 8.
    Hassan HH, Denis M, Lee DY et al (2007) Identification of an ABCA1-dependent phospholipid-rich plasma membrane apolipoprotein A-I binding site for nascent HDL formation: implications for current models of HDL biogenesis. J Lipid Res 48:2428–2442CrossRefPubMedGoogle Scholar
  9. 9.
    He X, Huang CL, Schuchman EH (2009) Quantitative analysis of sphingosine-1-phosphate by HPLC after napthalene-2,3-dicarboxaldehyde (NDA) derivatization. J Chromatogr B Analyt Technol Biomed Life Sci 877:983–990CrossRefPubMedGoogle Scholar
  10. 10.
    Heo K, Park KA, Kim YH et al (2009) Sphingosine 1-phosphate induces vascular endothelial growth factor expression in endothelial cells. BMB Rep 42:685–690CrossRefPubMedGoogle Scholar
  11. 11.
    Hla T, Lee MJ, Ancellin N, Paik JH, Kluk MJ (2001) Lysophospholipids—receptor revelations. Science 294:1875–1878CrossRefPubMedGoogle Scholar
  12. 12.
    Hla T, Venkataraman K, Michaud J (2008) The vascular S1P gradient-cellular sources and biological significance. Biochim Biophys Acta 1781:477–482CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Kimura T, Sato K, Kuwabara A et al (2001) Sphingosine 1-phosphate may be a major component of plasma lipoproteins responsible for the cytoprotective actions in human umbilical vein endothelial cells. J Biol Chem 276:31780–31785CrossRefPubMedGoogle Scholar
  14. 14.
    Kobayashi N, Kobayashi N, Yamaguchi A, Nishi T (2009) Characterization of the ATP-dependent sphingosine 1-phosphate transporter in rat erythrocytes. J Biol Chem 284:21192–21200CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Kobayashi N, Nishi T, Hirata T et al (2006) Sphingosine 1-phosphate is released from the cytosol of rat platelets in a carrier-mediated manner. J Lipid Res 47:614–621CrossRefPubMedGoogle Scholar
  16. 16.
    Lee YM, Venkataraman K, Hwang SI, Han DK, Hla T (2007) A novel method to quantify sphingosine 1-phosphate by immobilized metal affinity chromatography (IMAC). Prostaglandins Other Lipid Mediat 84:154–162CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Liu X, Xiong SL, Yi GH (2012) ABCA1, ABCG1, and SR-BI: transit of HDL-associated sphingosine-1-phosphate. Clin Chim Acta 413:384–390CrossRefPubMedGoogle Scholar
  18. 18.
    Liu X, Zhang QH, Yi GH (2012) Regulation of metabolism and transport of sphingosine-1-phosphate in mammalian cells. Mol Cell Biochem 363:21–33CrossRefPubMedGoogle Scholar
  19. 19.
    Mitra P, Oskeritzian CA, Payne SG, Beaven MA, Milstien S, Spiegel S (2006) Role of ABCC1 in export of sphingosine-1-phosphate from mast cells. Proc Natl Acad Sci U S A 103:16394–16399CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Murata N, Sato K, Kon J et al (2000) Interaction of sphingosine 1-phosphate with plasma components, including lipoproteins, regulates the lipid receptor-mediated actions. Biochem J 352(Pt 3):809–815CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Pitson SM, Xia P, Leclercq TM et al (2005) Phosphorylation-dependent translocation of sphingosine kinase to the plasma membrane drives its oncogenic signalling. J Exp Med 201:49–54CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Rhode S, Breuer A, Hesse J et al (2004) Visualization of the uptake of individual HDL particles in living cells via the scavenger receptor class B type I. Cell Biochem Biophys 41:343–356CrossRefPubMedGoogle Scholar
  23. 23.
    Sato K, Malchinkhuu E, Horiuchi Y et al (2007) Critical role of ABCA1 transporter in sphingosine 1-phosphate release from astrocytes. J Neurochem 103:2610–2619PubMedGoogle Scholar
  24. 24.
    Seetharam D, Mineo C, Gormley AK et al (2006) High-density lipoprotein promotes endothelial cell migration and reendothelialization via scavenger receptor-B type I. Circ Res 98:63–72CrossRefPubMedGoogle Scholar
  25. 25.
    Sekine Y, Suzuki K, Remaley AT (2011) HDL and sphingosine-1-phosphate activate stat3 in prostate cancer DU145 cells via ERK1/2 and S1P receptors, and promote cell migration and invasion. Prostate 71:690–699CrossRefPubMedGoogle Scholar
  26. 26.
    Spiegel S, Milstien S (2003) Sphingosine-1-phosphate: an enigmatic signalling lipid. Nat Rev Mol Cell Biol 4:397–407CrossRefPubMedGoogle Scholar
  27. 27.
    Stahelin RV, Hwang JH, Kim JH et al (2005) The mechanism of membrane targeting of human sphingosine kinase 1. J Biol Chem 280:43030–43038CrossRefPubMedGoogle Scholar
  28. 28.
    Strub GM, Paillard M, Liang J et al (2011) Sphingosine-1-phosphate produced by sphingosine kinase 2 in mitochondria interacts with prohibitin 2 to regulate complex IV assembly and respiration. FASEB J 25:600–612CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Thuahnai ST, Lund-Katz S, Williams DL, Phillips MC (2001) Scavenger receptor class B, type I-mediated uptake of various lipids into cells. Influence of the nature of the donor particle interaction with the receptor. J Biol Chem 276:43801–43808CrossRefPubMedGoogle Scholar
  30. 30.
    Vaughan AM, Tang C, Oram JF (2009) ABCA1 mutants reveal an interdependency between lipid export function, apoA-I binding activity, and Janus kinase 2 activation. J Lipid Res 50:285–292CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Venkataraman K, Lee YM, Michaud J et al (2008) Vascular endothelium as a contributor of plasma sphingosine 1-phosphate. Circ Res 102:669–676CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Zhu W, Saddar S, Seetharam D et al (2008) The scavenger receptor class B type I adaptor protein PDZK1 maintains endothelial monolayer integrity. Circ Res 102:480–487CrossRefPubMedGoogle Scholar

Copyright information

© University of Navarra 2016

Authors and Affiliations

  • Xing Liu
    • 1
  • Kun Ren
    • 1
  • Rong Suo
    • 1
  • Sheng-Lin Xiong
    • 2
  • Qing-Hai Zhang
    • 3
  • Zhong-Cheng Mo
    • 4
  • Zhen-Li Tang
    • 1
  • Yue Jiang
    • 1
  • Xiao-Shan Peng
    • 1
  • Guang-Hui Yi
    • 1
    Email author
  1. 1.Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan ProvinceUniversity of South ChinaHengyang CityChina
  2. 2.You Country People’s HospitalZhuzhouChina
  3. 3.Clinical Research Institution, The First Affiliated HospitalUniversity of South ChinaHengyangChina
  4. 4.Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Life Science Research CenterUniversity of South ChinaHengyangChina

Personalised recommendations