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

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 Dannenberg, Tobias Buschmann, Philipp Westhoff, Amin Polzin, Malte Kelm, Petra Keul, Sarah Weske and Bodo Levkau ()
Additional contact information
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
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

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-44109-x

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