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 receptor β/δ (PPARβ/δ) protects against ceramide-induced cellular toxicity in rat brain astrocytes and neurons by activation of ceramide kinase
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DOI：
10.1016/j.mcn.2014.01.008
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发表时间：
2014-03-01
影响因子：
3.5
通讯作者：
Reiser, Georg
中科院分区：
文献类型：
--
作者：
Aleshin, Stepan;Reiser, Georg
过氧化物酶体增殖物激活受体（PPARs）是核受体超家族的重要成员。这些核受体（PPAR α、β/δ和γ）的配体属于广泛的亲脂性物质。尽管在神经系统疾病模型中证实了PPARbeta/delta的神经保护功效，但与PPARalpha和PPARgamma相比，对大脑中PPARbeta/delta的生物学研究少得多。在目前的研究中，我们测试的假设，由过氧化物酶体增殖物激活受体β/δ诱导的神经保护作用可能依赖于神经酰胺代谢的调节。我们发现，与PPAR β/δ激动剂L-165041预孵育的神经细胞对神经酰胺诱导的细胞死亡产生显着的保护作用。最重要的是，L-165041不仅在损伤之前，而且在损伤开始之后保护神经酰胺诱导的细胞死亡。为了确定保护机制，我们表明L-165041上调神经细胞中的神经酰胺激酶（CerK）表达水平。与此一致，我们检测到CerK的药理学抑制降低了L-165041的保护作用。为了进一步解释保护机制，研究了星形胶质细胞中的基因敲除。在星形胶质细胞中敲低PPAR β/δ和CerK用于验证L-165041的保护作用是CerK和PPAR β/δ依赖性的。我们证明，在CerK或PPAR β/δ敲低的星形胶质细胞中，添加L-165041没有保护作用。因此，我们得出结论，PPARbeta/delta通过诱导和激活CerK保护神经细胞免受神经酰胺诱导的细胞死亡。(C)2014爱思唯尔公司All rights reserved.
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.