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 (PPAR alpha) 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 PPAR alpha and mHS expression in brain, implying that brain-targeted PPAR alpha activators may likewise up-regulate mHS expression in brain. Thus, to attempt pharmacological activation of brain PPAR alpha in vivo, we have administered to rats two drugs with previously defined actions in rat brain, namely the PPAR alpha-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 PPAR alpha-expressing organ. Furthermore, ciprofibrate potently increases mHS mRNA abundance in rat brain, together with lesser increases in two other PPAR alpha-regulated mRNAs. Thus we demonstrate, for the first time, up-regulation of expression of PPAR alpha-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.
Cullingford
Tim E
TE
Department of Clinical and Molecular Pharmacokinetics/Pharmacodynamics, Faculty of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan. teculling@cassius.demon.co.uk
Dolphin
Colin T
CT
Sato
Hitoshi
H
D042964:Acyl-CoA Dehydrogenase; D042962:Acyl-CoA Oxidase; D000818:Animals; D001921:Brain / Q000201:enzymology; D002995:Clofibric Acid / Q000031:analogs & derivatives / Q000494:pharmacology*; D003066:Coenzyme A Ligases / Q000096:biosynthesis*; D044943:Fatty Acid Desaturases / Q000096:biosynthesis; D005227:Fatty Acids / Q000096:biosynthesis*; D058607:Fibric Acids; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000502:physiology; D006904:Hydroxymethylglutaryl-CoA Synthase; D007659:Ketones / Q000378:metabolism; D008099:Liver / Q000201:enzymology; D008297:Male; D010084:Oxidation-Reduction / Q000187:drug effects; D010088:Oxidoreductases / Q000096:biosynthesis; D020025:Peroxisome Proliferators / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis*; D014157:Transcription Factors / Q000096:biosynthesis*; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology
D005227:Fatty Acids; D058607:Fibric Acids; D007659:Ketones; D020025:Peroxisome Proliferators; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D002995:Clofibric Acid; D010088:Oxidoreductases; D044943:Fatty Acid Desaturases; D042962:Acyl-CoA Oxidase; D042964:Acyl-CoA Dehydrogenase; D006904:Hydroxymethylglutaryl-CoA Synthase; D003066:Coenzyme A Ligases; C019304:ciprofibrate