The peroxisome proliferator-activated receptor α-selective activator ciprofibrate upregulates expression of genes encoding fatty acid oxidation and ketogenesis enzymes in rat brain
The peroxisome proliferator-activated receptor α-selective activator ciprofibrate upregulates expression of genes encoding fatty acid oxidation and ketogenesis enzymes in rat brain
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DOI：
10.1016/s0028-3908(02)00014-x
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发表时间：
2002-04-01
影响因子：
4.7
通讯作者：
Sato, H
中科院分区：
文献类型：
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作者：
Cullingford, TE;Dolphin, CT;Sato, H
激活的过氧化物酶体增殖物激活受体 α (PPARα) 可防止细胞炎症反应，并且是脂肪酸介导的编码关键生酮酶线粒体 3-羟基-3-甲基戊二酰辅酶 A 合酶 (mHS) 基因上调的核心。我们之前已经证明了大脑中 PPARa 和 mHS 的表达，这意味着针对大脑的 PPARα 激活剂可能同样上调大脑中 mHS 的表达。因此，尝试药理激活大脑 PPARα。在体内，我们给大鼠施用了两种在大鼠大脑中具有先前定义的作用的药物，即PPARα选择性激活剂环丙贝特和泛PPAR激活剂丙戊酸盐。使用灵敏且具有辨别力的 RNase 保护联合测定，我们证明环丙贝特和丙戊酸钠均可诱导肝脏（典型的 PPARα 表达器官）中的 mHS 表达。此外，环丙贝特可有效增加大鼠大脑中 mHS mRNA 的丰度，同时对其他两种 PPARα 调节的 mRNA 的增加也较少。因此，我们首次证明了大脑中 PPARα 依赖性基因（包括 mHS）表达的上调，这对神经炎症脂质的消除增加以及神经保护性酮体的产生增加产生了影响。 (C) 2002 Elsevier Science Ltd. 保留所有权利。
Activated peroxisome proliferator activated receptor alpha (PPARalpha) protects against the cellular inflammatory response, and is central to fatty acid-mediated upregulation of the gene encoding the key ketogenic enzyme mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (mHS). We have previously demonstrated both PPARa and mHS expression in brain, implying that brain-targeted PPARalpha activators may likewise up-regulate mHS expression in brain. Thus, to attempt pharmacological activation of brain PPARalpha. in vivo, we have administered to rats two drugs with previously defined actions in rat brain, namely the PPARalpha-selective activator ciprofibrate and the pan-PPAR activator valproate. Using the sensitive and discriminatory RNase protection co-assay, we demonstrate that both ciprofibrate and valproate induce mHS expression in liver, the archetypal PPARalpha-expressing organ. Furthermore, ciprofibrate potently increases mHS mRNA abundance in rat brain, together with lesser increases in two other PPARalpha-regulated mRNAs. Thus we demonstrate, for the first time, up-regulation of expression of PPARalpha-dependent genes including mHS in brain, with implications in the increased elimination of neuro-inflammatory lipids and concomitant increased production of neuro-protective ketone bodies. (C) 2002 Elsevier Science Ltd. All rights reserved.