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Sphingosine-1-phosphate suppresses GLUT activity through PP2A and counteracts hyperglycemia in diabetic red blood cells

Author

Listed:
  • Nadine Thomas

    (Heinrich Heine University)

  • Nathalie H. Schröder

    (Heinrich Heine University)

  • Melissa K. Nowak

    (Heinrich Heine University)

  • Philipp Wollnitzke

    (Heinrich Heine University)

  • Shahrooz Ghaderi

    (Heinrich Heine University)

  • Karin Wnuck Lipinski

    (Heinrich Heine University)

  • Annalena Wille

    (Heinrich Heine University)

  • Jennifer Deister-Jonas

    (Heinrich Heine University)

  • Jens Vogt

    (Heinrich Heine University)

  • Markus H. Gräler

    (Jena University Hospital
    Jena University Hospital)

  • Lisa Dannenberg

    (University Hospital Düsseldorf)

  • Tobias Buschmann

    (Heinrich Heine University)

  • Philipp Westhoff

    (Heinrich Heine University)

  • Amin Polzin

    (University Hospital Düsseldorf)

  • Malte Kelm

    (University Hospital Düsseldorf)

  • Petra Keul

    (Heinrich Heine University)

  • Sarah Weske

    (Heinrich Heine University)

  • Bodo Levkau

    (Heinrich Heine University
    Medical Faculty and University Hospital)

Abstract

Red blood cells (RBC) are the major carriers of sphingosine-1-phosphate (S1P) in blood. Here we show that variations in RBC S1P content achieved by altering S1P synthesis and transport by genetic and pharmacological means regulate glucose uptake and metabolic flux. This is due to S1P-mediated activation of the catalytic protein phosphatase 2 (PP2A) subunit leading to reduction of cell-surface glucose transporters (GLUTs). The mechanism dynamically responds to metabolic cues from the environment by increasing S1P synthesis, enhancing PP2A activity, reducing GLUT phosphorylation and localization, and diminishing glucose uptake in RBC from diabetic mice and humans. Functionally, it protects RBC against lipid peroxidation in hyperglycemia and diabetes by activating the pentose phosphate pathway. Proof of concept is provided by the resistance of mice lacking the S1P exporter MFSD2B to diabetes-induced HbA1c elevation and thiobarbituric acid reactive substances (TBARS) generation in diabetic RBC. This mechanism responds to pharmacological S1P analogues such as fingolimod and may be functional in other insulin-independent tissues making it a promising therapeutic target.

Suggested Citation

  • Nadine Thomas & Nathalie H. Schröder & Melissa K. Nowak & Philipp Wollnitzke & Shahrooz Ghaderi & Karin Wnuck Lipinski & Annalena Wille & Jennifer Deister-Jonas & Jens Vogt & Markus H. Gräler & Lisa D, 2023. "Sphingosine-1-phosphate suppresses GLUT activity through PP2A and counteracts hyperglycemia in diabetic red blood cells," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-44109-x
    DOI: 10.1038/s41467-023-44109-x
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    References listed on IDEAS

    as
    1. Thiet M. Vu & Ayako-Nakamura Ishizu & Juat Chin Foo & Xiu Ru Toh & Fangyu Zhang & Ding Ming Whee & Federico Torta & Amaury Cazenave-Gassiot & Takayoshi Matsumura & Sangho Kim & Sue-Anne E. S. Toh & To, 2017. "Mfsd2b is essential for the sphingosine-1-phosphate export in erythrocytes and platelets," Nature, Nature, vol. 550(7677), pages 524-528, October.
    2. Kaiqi Sun & Yujin Zhang & Angelo D’Alessandro & Travis Nemkov & Anren Song & Hongyu Wu & Hong Liu & Morayo Adebiyi & Aji Huang & Yuan E. Wen & Mikhail V. Bogdanov & Alejandro Vila & John O’Brien & Rod, 2016. "Sphingosine-1-phosphate promotes erythrocyte glycolysis and oxygen release for adaptation to high-altitude hypoxia," Nature Communications, Nature, vol. 7(1), pages 1-13, November.
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