Identifying novel molecular mechanisms of medium-chain fatty acids using the model Dictyostelium discoideum

The medium-chain triglyceride (MCT) ketogenic diet is a high fat diet used to prevent seizures in patients with drug resistant epilepsy. In addition, there is emerging evidence that the MCT diet could be useful in other areas of health and medicine, however, the molecular mechanisms behind these effects are poorly understood. In this study, the tractable model organism, Dictyostelium discoideum, was employed to investigate novel mechanisms of action of the two medium-chain fatty acids, decanoic acid and octanoic acid, provided by the diet. A non-biased genetic screen was utilised to identify a mechanism of decanoic acid dependent upon the activity of a ubiquitin regulatory X (UBX) domain containing protein (UBXD18). Investigating this mechanism identified that UBXD18-GFP interacts with the ubiquitous protein p97(-RFP), where decanoic acid inhibited p97(-RFP) activity in a UBXD18 dependent manner. Due to the role of p97 in regulating homeostasis through autophagy, the effects of both decanoic acid and octanoic acid on this pathway were investigated, with both fatty acids demonstrated to activate autophagy independently of UBXD18. To investigate this further, decanoic acid was found to inhibit the major regulator of autophagy, mTORC1, a process linked to a range of positive medical and health related effects. This effect on mTORC1 was shown to be specific for decanoic acid, and thus supports a model where decanoic acid acts through UBXD18 dependent inhibition of p97 to reduce mTORC1 signalling. Finally, the inhibitory effect of decanoic acid on mTORC1 was shown to be conserved in a rat hippocampal slice model and in tuberous sclerosis complex (TSC) patient-derived astrocytes. Thus, this study provides a novel therapeutic approach to down-regulate mTORC1 signalling and activate autophagy through dietary decanoic acid intake, with potential relevance for a wide range of medical treatments.