Heptanoate as a neural fuel: energetic and neurotransmitter precursors in normal and glucose transporter I-deficient (G1D) brain.
It has been postulated that triheptanoin can ameliorate seizures by supplying the tricarboxylic acid cycle with both acetyl-CoA for energy production and propionyl-CoA to replenish cycle intermediates. These potential effects may also be important in other disorders associated with impaired glucose metabolism because glucose supplies, in addition to acetyl-CoA, pyruvate, which fulfills biosynthetic demands via carboxylation. In patients with glucose transporter type I deficiency (G1D), ketogenic diet fat (a source only of acetyl-CoA) reduces seizures, but other symptoms persist, providing the motivation for studying heptanoate metabolism. In this work, metabolism of infused [5,6,7-(13)C(3)]heptanoate was examined in the normal mouse brain and in G1D by (13)C-nuclear magnetic resonance spectroscopy, gas chromatography-mass spectrometry (GC-MS), and liquid chromatography-mass spectrometry (LC-MS). In both groups, plasma glucose was enriched in (13)C, confirming gluconeogenesis from heptanoate. Acetyl-CoA and glutamine levels became significantly higher in the brain of G1D mice relative to normal mice. In addition, brain glutamine concentration and (13)C enrichment were also greater when compared with glutamate in both animal groups, suggesting that heptanoate and/or C5 ketones are primarily metabolized by glia. These results enlighten the mechanism of heptanoate metabolism in the normal and glucose-deficient brain and encourage further studies to elucidate its potential antiepileptic effects in disorders of energy metabolism.
Rare Brain Disorders Clinic and Laboratory, Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8813, USA.
Isaac
I
Marin-Valencia
Levi B
LB
Good
Qian
Q
Ma
Craig R
CR
Malloy
Juan M
JM
Pascual
D000105:Acetyl Coenzyme A / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry / Q000187:drug effects / Q000235:genetics; D004734:Energy Metabolism; D005947:Glucose / Q000235:genetics / Q000378:metabolism*; D051272:Glucose Transporter Type 1; D005973:Glutamine / Q000235:genetics / Q000378:metabolism*; D006537:Heptanoates / Q000378:metabolism* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008822:Mice, Transgenic; D019289:Pyruvic Acid / Q000378:metabolism; D012640:Seizures / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000494:pharmacology
D000927:Anticonvulsants; D051272:Glucose Transporter Type 1; D006537:Heptanoates; C495678:Slc2a1 protein, mouse; D014280:Triglycerides; D005973:Glutamine; C531010:triheptanoin; D000105:Acetyl Coenzyme A; D019289:Pyruvic Acid; D005947:Glucose