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Effects of medium chain fatty acids and ketones on leucine metabolism in astrocytes : towards an understanding of the anti-epileptic efficacy of the ketogenic diet Townsend, Marria May


A high fat, low glucose diet, termed "ketogenic" because it results in elevations in circulating ketones, has been used for over 75 years as a treatment for pediatric epilepsy. The mechanism by which the ketogenic diet suppresses epileptic seizures is not understood. Fundamentally, the diet must involve an effect on brain metabolism but there is a lack of information about the metabolic impact of a change in fuel source at the level of the brain cell. This study examined the effect of medium chain fatty acids (MCFA) and ketones on the oxidation of leucine in astrocytes. The first series of experiments measured the production of 14CO2, from [U14C]-leucine, in the presence of no additional substrate (control) and increasing concentrations of octanoate (an MCFA) and p-hydroxybutyrate. The second series of experiments measured 14CO2 production from oxidative decarboxylation of [1-14C]-leucine and 14CO2 production from the chemical decarboxylation of [1-14C]-leucine derived α-ketoisocaproate (α-KIC) in the presence and absence of β-hydroxybutyrate and octanoate. Inclusion of β-hydroxybutyrate caused a 60-70% reduction in 14CO2 production from [U-14C]-leucine; with octanoate the inhibition was even more dramatic with 80% reduction compared to control. Experiments using [1-14C]- leucine did not find a statistically significant change in 14CO2 production when β-hydroxybutyrate was included, but did find an increased level of labelled α-KIC in the media, reflecting leucine that had been transaminated but had not proceeded through to the second step of metabolism. The amount of residual α-KIC was increased by up to 54%. Octanoate did inhibit oxidative decarboxylation of [1-14C]-leucine, with 5.0 mM octanoate reducing the production of 14CO2 by 94%. In contrast to the accumulation of α-KIC seen in experiments using β-hydroxybutyrate, incubation with octanoate resulted in a decreased production of α-KIC. This finding suggests that octanoate and β-hydroxybutyrate may inhibit leucine metabolism by different mechanisms. These findings support the hypothesis that MCFAs and ketones alter leucine metabolism in astrocytes. They may have implications for the understanding of integrated fuel metabolism within the brain and for the mechanism of action of the ketogenic diet. [Scientific formulae used in this abstract could not be reproduced.]

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