The ketogenic diet upregulates expression of the gene encoding the key ketogenic enzyme mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase in rat brain.
The ketogenic diet is a clinically and experimentally effective anti-epileptic treatment whose molecular mechanism(s) of action remain to be elucidated. As a first step in defining its effects on regulation of fatty acid oxidation and ketogenesis at the genetic level, we have administered to rats: (1) a calorie-restricted ketogenic diet (KCR); (2) a calorie-restricted normal diet (NCR); or (3) a normal diet ad libitum (NAL). We have used RNase protection to co-assay diet-induced changes in abundance of the mRNA encoding the critical enzyme of ketogenesis from acetyl-CoA namely mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (mHS) in liver and brain, together with mRNAs encoding three other key enzymes of fatty acid oxidation. We demonstrate that NCR-fed rats exhibit a significant 2-fold increase in liver mHS mRNA compared to NAL-fed rats, and that KCR-fed rats exhibit a significant 2-fold increase in both liver and brain mHS mRNA compared to NAL-fed rats. Our results demonstrate, for the first time, the effect of a ketogenic diet on gene expression in brain, and suggest possible anti-epileptic mechanisms for future investigation.
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@hotmail.com
Eagles
Douglas A
DA
Sato
Hitoshi
H
D000214:Acyl Coenzyme A / Q000235:genetics*; D042964:Acyl-CoA Dehydrogenase; D042962:Acyl-CoA Oxidase; D000818:Animals; D001921:Brain / Q000502:physiology*; D003066:Coenzyme A Ligases / Q000235:genetics; D003292:Convulsants; D004032:Diet; D002149:Energy Intake; D044943:Fatty Acid Desaturases / Q000235:genetics; D015870:Gene Expression; D007657:Ketone Bodies / Q000096:biosynthesis*; D008099:Liver / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000201:enzymology*; D010088:Oxidoreductases / Q000235:genetics; D010433:Pentylenetetrazole; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control; D015854:Up-Regulation
D000214:Acyl Coenzyme A; D003292:Convulsants; D007657:Ketone Bodies; D012333:RNA, Messenger; C008047:3-hydroxy-3-methylglutaryl-coenzyme A; D010088:Oxidoreductases; D044943:Fatty Acid Desaturases; D042962:Acyl-CoA Oxidase; D042964:Acyl-CoA Dehydrogenase; D003066:Coenzyme A Ligases; C403665:ACSL6 protein, human; D010433:Pentylenetetrazole