Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) protects against ceramide-induced cellular toxicity in rat brain astrocytes and neurons by activation of ceramide kinase

Peroxisome proliferator-activated receptors (PPARs) are important members of the nuclear receptor superfamily. Ligands of these nuclear receptors (PPAR alpha, beta/delta and gamma) belong to a wide range of lipophilic substances. In spite of the proven neuroprotective efficacy of PPAR beta/delta in models of neurological diseases, the biology of PPAR beta/delta in the brain has been much less investigated than that of PPAR alpha and PPAR gamma. In the present study, we test the hypothesis that neuroprotection induced by PPAR beta/delta could rely on the regulation of ceramide metabolism. We found that preincubation of neural cells with the PPAR beta/delta agonist L-165041 exerts significant protection against ceramide-induced cell death. Most importantly, L-165041 protects against ceramide-induced cell death not only before the insult, but also after the onset of the insult. To identify the mechanism of protection, we show that L-165041 upregulates ceramide kinase (CerK) expression levels in neural cells. Consistent with that, we detected that pharmacological inhibition of CerK reduces the protective effects of L-165041. To further decipher the mechanism of protection, gene knockdown in astrocytes was studied. Knockdown of PPAR beta/delta and CerK in astrocytes was used to verify that the protective effects of L-165041 are CerK-and PPAR beta/delta dependent. We demonstrate that in CerK- or PPAR beta/delta-knockdown astrocytes, addition of L-165041 has no protective effect. Thus, we conclude that PPAR beta/delta protects neural cells against ceramide-induced cell death via induction and activation of CerK. (C) 2014 Elsevier Inc. All rights reserved.