Fig. 8: Proposed mechanism for lipid metabolism regulation in SCs upon injury.

a After injury, SCs switch from a myelinating (dark green) to a repair (light green) phenotype. In human SCs (red area), induction of the repair SC phenotype is decreased or at least delayed, which might lead to impaired regeneration and delayed re-differentiation compared to murine SCs (grey area). b In murine repair SCs, PPARg expression is down-regulated after injury. In addition, intracellular S1P is decreased which might involve enhanced enzymatic degradation to PE and HD by the enzyme SGPL1. Both, decreased PPARg and S1P levels result in blunted PPARg activity, which in turn leads to decreased expression of lipid metabolism associated genes. Pharmacological repression of PPARg activity in human SCs by SR and GW decreased lipogenic gene transcription. c Later during regeneration SCs re-differentiate into myelinating SCs. In this case PPARg expression and S1P levels have to be raised again, thereby enhancing PPARg activity and lipogenic gene expression. Pharmacological elevation of S1P by DOP-, THI-, C31-mediated SGPL1 inhibition, as well as PIO-mediated PPARg activation were able elevate lipogenic gene transcription and led to suppression of the repair SC phenotype. C31 (compound 31), DOP (4-deoxypyridoxine), GW (GW9662), HD (hexadecanal), PE (phosphoethanolamine), PIO (pioglitazone), PPARg (peroxisome proliferator-activated receptor gamma), S1P (sphingosine-1 phosphate), SC (Schwann cells), SGPL1 (sphingosine-1 phosphate lyase 1), SR (SR16832) and THI (2-acetyl-5-tetrahydroxybutyl imidazole).