Aziza Khabbush1, Michael Orford1, Yi-Chen Tsai2, Tricia Rutherford3, Maura O'Donnell3, Simon Eaton4, Simon J R Heales1,5,6. 1. Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London, United Kingdom. 2. Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. 3. Vitaflo International, Liverpool, United Kingdom. 4. Paediatric Surgery, UCL Great Ormond Street Institute of Child Health, London, United Kingdom. 5. Chemical Pathology, Great Ormond Street for Children Hospital NHS Foundation Trust, London, United Kingdom. 6. Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, London, United Kingdom.
Abstract
OBJECTIVE: The medium-chain triglyceride (MCT) ketogenic diet contains both octanoic (C8) and decanoic (C10) acids. The diet is an effective treatment for pharmacoresistant epilepsy. Although the exact mechanism for its efficacy is not known, it is emerging that C10, but not C8, interacts with targets that can explain antiseizure effects, for example, peroxisome proliferator-activated receptor-γ (eliciting mitochondrial biogenesis and increased antioxidant status) and the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor. For such effects to occur, significant concentrations of C10 are likely to be required in the brain. METHODS: To investigate how this might occur, we measured the β-oxidation rate of 13 C-labeled C8 and C10 in neuronal SH-SY5Y cells using isotope-ratio mass spectrometry. The effects of carnitine palmitoyltransferase I (CPT1) inhibition, with the CPT1 inhibitor etomoxir, on C8 and C10 β-oxidation were also investigated. RESULTS: Both fatty acids were catabolized, as judged by 13 CO2 release. However, C10 was β-oxidized at a significantly lower rate, 20% that of C8. This difference was explained by a clear dependence of C10 on CPT1 activity, which is low in neurons, whereas 66% of C8 β-oxidation was independent of CPT1. In addition, C10 β-oxidation was decreased further in the presence of C8. SIGNIFICANCE: It is concluded that, because CPT1 is poorly expressed in the brain, C10 is relatively spared from β-oxidation and can accumulate. This is further facilitated by the presence of C8 in the MCT ketogenic diet, which has a sparing effect upon C10 β-oxidation. Wiley Periodicals, Inc.
OBJECTIVE: The medium-chain triglyceride (MCT) ketogenic diet contains both octanoic (C8) and decanoic (C10) acids. The diet is an effective treatment for pharmacoresistant epilepsy. Although the exact mechanism for its efficacy is not known, it is emerging that C10, but not C8, interacts with targets that can explain antiseizure effects, for example, peroxisome proliferator-activated receptor-γ (eliciting mitochondrial biogenesis and increased antioxidant status) and the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor. For such effects to occur, significant concentrations of C10 are likely to be required in the brain. METHODS: To investigate how this might occur, we measured the β-oxidation rate of 13 C-labeled C8 and C10 in neuronal SH-SY5Y cells using isotope-ratio mass spectrometry. The effects of carnitine palmitoyltransferase I (CPT1) inhibition, with the CPT1 inhibitor etomoxir, on C8 and C10 β-oxidation were also investigated. RESULTS: Both fatty acids were catabolized, as judged by 13 CO2 release. However, C10 was β-oxidized at a significantly lower rate, 20% that of C8. This difference was explained by a clear dependence of C10 on CPT1 activity, which is low in neurons, whereas 66% of C8 β-oxidation was independent of CPT1. In addition, C10 β-oxidation was decreased further in the presence of C8. SIGNIFICANCE: It is concluded that, because CPT1 is poorly expressed in the brain, C10 is relatively spared from β-oxidation and can accumulate. This is further facilitated by the presence of C8 in the MCT ketogenic diet, which has a sparing effect upon C10 β-oxidation. Wiley Periodicals, Inc.
Authors: Lijing Xin; Özlem Ipek; Maurice Beaumont; Maya Shevlyakova; Nicolas Christinat; Mojgan Masoodi; Norman Greenberg; Rolf Gruetter; Bernard Cuenoud Journal: Front Nutr Date: 2018-07-12
Authors: Benjamin A Berk; Tsz H Law; Rowena M A Packer; Annette Wessmann; Andrea Bathen-Nöthen; Tarja S Jokinen; Anna Knebel; Andrea Tipold; Ludovic Pelligand; Zoe Meads; Holger A Volk Journal: J Vet Intern Med Date: 2020-04-15 Impact factor: 3.333