Response of brain amino acid metabolism to ketosis.
Our objective was to study brain amino acid metabolism in response to ketosis. The underlying hypothesis is that ketosis is associated with a fundamental change of brain amino acid handling and that this alteration is a factor in the anti-epileptic effect of the ketogenic diet. Specifically, we hypothesize that brain converts ketone bodies to acetyl-CoA and that this results in increased flux through the citrate synthetase reaction. As a result, oxaloacetate is consumed and is less available to the aspartate aminotransferase reaction; therefore, less glutamate is converted to aspartate and relatively more glutamate becomes available to the glutamine synthetase and glutamate decarboxylase reactions. We found in a mouse model of ketosis that the concentration of forebrain aspartate was diminished but the concentration of acetyl-CoA was increased. Studies of the incorporation of 13C into glutamate and glutamine with either [1-(13)C]glucose or [2-(13)C]acetate as precursor showed that ketotic brain metabolized relatively less glucose and relatively more acetate. When the ketotic mice were administered both acetate and a nitrogen donor, such as alanine or leucine, they manifested an increased forebrain concentration of glutamine and GABA. These findings supported the hypothesis that in ketosis there is greater production of acetyl-CoA and a consequent alteration in the equilibrium of the aspartate aminotransferase reaction that results in diminished aspartate production and potentially enhanced synthesis of glutamine and GABA.
Yudkoff
Marc
M
Department of Pediatrics, University of Pennsylvania School of Medicine, Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104, USA. yudkoff@email.chop.edu
Daikhin
Yevgeny
Y
Nissim
Ilana
I
Horyn
Oksana
O
Lazarow
Adam
A
Luhovyy
Bohdan
B
Wehrli
Suzanne
S
Nissim
Itzhak
I
D000085:Acetates / Q000378:metabolism; D000105:Acetyl Coenzyme A / Q000378:metabolism*; D000596:Amino Acids / Q000096:biosynthesis*; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D001224:Aspartic Acid / Q000096:biosynthesis; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry / Q000502:physiology*; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D004734:Energy Metabolism / Q000502:physiology*; D005947:Glucose / Q000378:metabolism; D018698:Glutamic Acid / Q000096:biosynthesis; D005973:Glutamine / Q000096:biosynthesis; D007662:Ketosis / Q000378:metabolism*; D008297:Male; D051379:Mice; D023421:Models, Animal; D062907:Oxaloacetic Acid / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000096:biosynthesis
D000085:Acetates; D000596:Amino Acids; D002250:Carbon Radioisotopes; D005973:Glutamine; D062907:Oxaloacetic Acid; D001224:Aspartic Acid; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D000105:Acetyl Coenzyme A; D001219:Aspartate Aminotransferases; D005947:Glucose