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

• Published in: Nature communications 2023-12, Vol.14 (1), p.8329-8329, Article 8329
• Main Authors: Thomas, Nadine, Schröder, Nathalie H., Nowak, Melissa K., Wollnitzke, Philipp, Ghaderi, Shahrooz, von Wnuck Lipinski, Karin, Wille, Annalena, Deister-Jonas, Jennifer, Vogt, Jens, Gräler, Markus H., Dannenberg, Lisa, Buschmann, Tobias, Westhoff, Philipp, Polzin, Amin, Kelm, Malte, Keul, Petra, Weske, Sarah, Levkau, Bodo
• Format: Article
• Language: English
• Subjects: 101/58; 13/31; 13/95; 631/443; 64; 64/60; 692/4017; 692/53/2421; 692/699/2743/137/773; Cell surface; Diabetes; Diabetes mellitus; Erythrocytes; Glucose; Glycolysis; Humanities and Social Sciences; Hyperglycemia; Lipid peroxidation; Lipids; Localization; Metabolic flux; Metabolism; multidisciplinary; Pentose; Pentose phosphate pathway; Peroxidation; Pharmacology; Phosphorylation; Protein phosphatase; Science; Science (multidisciplinary); Sphingosine 1-phosphate; Synthesis; Therapeutic targets; Thiobarbituric acid
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-44109-x

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. Red blood cells (RBC) carry the majority of sphingosine-1-phosphate (S1P). Here, the authors show that RBC dynamically regulate S1P levels in response to metabolic stress and employ them to regulate glucose uptake, glycolysis and the pentose phosphate pathway as protection against lipid peroxidation.