New information  about branched chain amino acids and epilepsy.

Triheptanoin oil and odd-carbon fatty acids

Fatty acids are comprised of chains of carbon atoms with a carboxylic acid at the end.  Two properties of fatty acid are generally considered when talking about fatty acids.  This is their length, the number of carbon atoms, and degree of unsaturation, or the number of carbon-carbon double bonds in the chain.  One other property that is not given as much attention, especially in normal diets, is whether or not a fatty acid chain contains an even or an odd number of carbon atoms.  This difference between even- and odd- carbon fatty acids becomes important during fasting, and with a ketogenic diet.

In terms of physiology, the main feature off odd-carbon fatty acids is that they can be converted to the intermediate molecule of the TCA (or Citric Acid) cycle, and even-carbon fatty acids cannot.  This distinction is not important under normal dietary conditions because TCA intermediates are produced from glucose, primarily through the enzyme pyruvate carboxylase.  When glucose is limited during fasting or with a ketogenic diet, TCA intermediates must be supplied by different means.  The two other substrates for the TCA cycle are gluconeogenic amino acids and odd-carbon fatty acids. (See my updated page on branched chain amino acids and epilepsy)

Odd-Carbon Fatty Acids and the Central Nervous System

The central nervous system relies on a unique metabolic coupling between two types of cells- neurons and non-neuronal support cells called glia.  Neurons do not have the major anaplerotic enzyme, pyruvate carboxylase so do not make TCA cycle intermediates directly from glucose.  However glia make large amounts of the amino acid glutamine which is then transferred to neurons.  In neurons glutamine can be used to fill the TCA pool.  Glucose is the primary energy source for the brain since fats cannot cross the blood brain barrier.  During fasting or a ketogenic diet, fats are converted to ketones which can enter the brain and be used for energy.  Odd-carbon amino acids and even carbon amino acids differ in terms of what ketone bodes are produced during ketosis.  Even-carbon fatty acids are converted to four carbon (C4) ketones- acetoacetate and beta-hydroxyburyrate.  These ketones are produced from odd-carbon fatty acids, but in addition odd-carbon fatty acids also produce five-carbon (C5) ketone bodies 3-hydroxypentanoate (BHP) and 3-ketopentanoate (BKP) .  Similar to the oxidation of fatty acids, C4 ketones cannot be turned in to TCA cycle intermediates, but C5 ketones can.  Both C4 and C5 ketones rapidly enter the brain across the blood brain barrier, and in this way odd-carbon fatty acids can supply anaplerotic molecules directly to neurons.

Triheptanoin oil

Triheptanoin in a triglyceride, which means that it consists of three fatty acids connected to a glycerol backbone.  This combination of having 3 odd-carbon fatty acid chains that are of a medium length means that a large number of anaplerotic molecules are produce from each triheptanoin triglyceride.  These properties have made it usefully clinically.  Triheptanoin is currently being used to treat pyruvate carboxylate deficiency in humans.  More recently animal studies have shown that a ketogenic diet high in triheptanoin is more effective than a regular ketogenic diet at slowing a hallmark of epilepsy called cortical spreading depression.  It is interesting that both the ketogenic diet and 2-deoxyglucose both reduce cortical spreading depression, suggesting the mechanism of action is the same.

Relationship of Triheptanoin to Ketogenic Diet and 2-Deoxyglucose.

My Model of the anti-epileptic properties of the ketogenic diet and 2-DG is based on an increased flux through the enzyme phosphoenolpyruvate carboxykinase (PEPCK).  PEPCK is and cataplerotic enzyme, meaning that it reduces the number of TCA cycle intermediates.  The size of the pool of TCA cycle intermediates is tightly controlled.  So over the long run the number of TCA cycle intermediates being made equals the number of TCA cycle intermediates being degraded, or anaplerosis=cataplerosis.  One prediction from my model is that supplying neurons with anaperotic substrates, such as triheptanoin would increase the flux through PEPCK and increase the efficacy of the Ketogenic Diet.

Effects of short-term and long-term treatment with medium- and long-chain triglycerides ketogenic diet on cortical spreading depression in young rats.
de Almeida Rabello Oliveira M, da Rocha Ataíde T, de Oliveira SL, de Melo Lucena AL, de Lira CE, Soares AA, de Almeida CB, Ximenes-da-Silva A.
Neurosci Lett. 2008 Mar 21;434(1):66-70.

Pyruvate carboxylase deficiency: clinical and biochemical response to anaplerotic diet therapy.
Mochel F, DeLonlay P, Touati G, Brunengraber H, Kinman RP, Rabier D, Roe CR, Saudubray JM.
Mol Genet Metab. 2005 Apr;84(4):305-12.

Fructose-1,6-bisphosphate has anticonvulsant activity in models of acute seizures in adult rats.
Lian XY, Khan FA, Stringer JL.
J Neurosci. 2007 Oct 31;27(44):12007-11

Calorie restriction and ketogenic diet diminish neuronal excitability in rat dentate gyrus in vivo.
Bough KJ, Schwartzkroin PA, Rho JM.
Epilepsia. 2003 Jun;44(6):752-60.

Parenteral and enteral metabolism of anaplerotic triheptanoin in normal rats
Renée P. Kinman,1,2 Takhar Kasumov,2 Kathryn A. Jobbins,2 Katherine R. Thomas,2 Jillian E. Adams,2 Lisa N. Brunengraber,2 Gerd Kutz,3 Wolf-Ulrich Brewer,4 Charles R. Roe,5 and Henri Brunengraber
Am J Physiol Endocrinol Metab 291: E860-E866, 2006.
Copyright 2011 Steve Kriegler