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Metabolic consequences of cellular exposure to decanoic acid

Khabbush, Aziza; (2018) Metabolic consequences of cellular exposure to decanoic acid. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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The medium-chain triglyceride ketogenic diet (MCT KD) is an effective treatment for drug-resistant epilepsy. However, its complexity and associated side effects necessitate the need for improved therapeutic strategies. Although the exact mechanisms for its efficacy remain unknown, there is a growing interest in the potential roles of mediumchain fatty acids octanoic (C8) and decanoic (C10) acids, present in MCT oil administered in the diet and found to be elevated in patient plasma. Moreover, it is emerging that C10, but not C8, elicits anti-seizure effects, inhibits AMPA receptor, and enhances neuronal catalase activity and mitochondrial biogenesis via peroxisome proliferator-activated receptor-γ (PPARγ). In this thesis, the biochemical and mitochondrial effects of C8 and C10 were further characterised in neuronal cell line SH-SY5Y, in addition to the effects of a C10-enriched MCT product in drug-resistant epilepsy patients. In cells treated for 6 days with 250μM of either fatty acid, C10, but not C8, was found to regulate mitochondrial content, as measured by mitochondrial enzyme marker citrate synthase (CS). The effect of C10 was observed to be dependent on control CS activity, increasing mitochondrial content in cells with low control levels and decreasing it in cells with high control activities. Furthermore, C10, but not C8, was found to raise mitochondrial membrane potential in cells, whilst neither of the two fatty acids were seen to affect cellular energy charge. The evidence suggests C10 may potentially optimise mitochondrial enrichment, generating mitochondria with increased function. For these effects to occur in the brain, however, significant concentrations are likely to be required. The neuronal β-oxidation rates of C8 and C10 were investigated and C10 β-oxidation was found to be significantly lower than that of C8. C10 β-oxidation was also found carnitine-dependent, whilst C8 was only partially dependent. In the presence of C8, C10 β-oxidation was further decreased. Consequently, C10 may be relatively spared from β-oxidation, permitting accumulation for it to exert its effects. In view of the evidence presented, the effects of a C10-enriched MCT product was examined in a feasibility study with drug-resistant epilepsy patients. Plasma levels of C8 and C10 were raised in participants. However, a lack of ketosis and no effects on blood lipid and acylcarnitine profiles were observed. Participants were found to have high baseline white blood cell CS activities, which decreased with treatment with the product. How these effects relate to seizure control remains to be determined, but the findings presented in this thesis suggest that a shift towards greater C10 enrichment in the MCT KD may be potentially beneficial.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Metabolic consequences of cellular exposure to decanoic acid
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Third party copyright material has been removed from the ethesis. Images identifying individuals have been redacted or partially redacted to protect their identity.
UCL classification: UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10053453
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