Impaired mitochondrial function is associated with a range of neurodegenerative disorders, making mitochondria important therapeutic targets. The ketogenic diet (KD) is often used in the treatment of pharmacoresistant epilepsy, but the underlying mechanisms responsible for its efficacy are yet to be elucidated. In this thesis, the role medium-chain fatty acids (MCFAs) have in contributing to the efficacy of the KD has been investigated. Mitochondrial enrichment and function were assessed after treatment of the human neuronal model SH-SY5Y cells with MCFAs. In contrast to treating cells for 6 days with either 250μM octanoic acid (C8) or dodecanoic acid (C12), 250μM decanoic acid (C10)-treated cells were found to exhibit a 30% increase in activity (p < 0.01) of the mitochondrial marker enzyme citrate synthase (CS), a 42% increase in respiratory chain complex I activity (p < 0.01), and a 31% increase in medium-chain acyl-CoA dehydrogenase activity (p < 0.05). Electron microscopy images provided further support for C10-induced mitochondrial biogenesis. Cellular antioxidant status appeared uncompromised by C10 treatment, as seen through measurements of cellular reduced glutathione. Peroxisome proliferator-activated receptor γ (PPARγ) has previously been shown to be partially activated by C10, and the findings presented in this thesis may implicate PPARγ activation as a potential mechanism for C10-induced mitochondrial biogenesis: Catalase, a peroxisomal marker enzyme, showed a 15% upregulation in activity (p < 0.05) following C10 treatment. Furthermore, BADGE, a PPARγ antagonist, was shown to diminish the C10-induced increases in both CS and catalase activity. RNA microarray analysis of SH-SY5Y cell gene expression, post-C10 treatment, found a number of changes as a result of treatment. The ability of C10 to downregulate many genes involved in cholesterol biosynthesis is of particular interest. The findings in this thesis may help shed some light on the unresolved mechanism through which the KD is able to induce mitochondrial biogenesis. Further work and understanding of C10 could aid the development of a clearer, less laborious, therapy to help replace the KD.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:639686 |
| Date | January 2015 |
| Creators | Hughes, S. D. |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1461165/ |
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