The peroxisome proliferator-activated receptor alpha-selective activator ciprofibrate upregulates expression of genes encoding fatty acid oxidation and ketogenesis enzymes in rat brain

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.