{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:05:02Z","timestamp":1785402302837,"version":"3.56.0"},"reference-count":88,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,10,29]],"date-time":"2021-10-29T00:00:00Z","timestamp":1635465600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Ketogenic diets, used in epilepsy treatment, are considered to work through reduced glucose and ketone generation to regulate a range of cellular process including autophagy induction. Recent studies into the medium-chain triglyceride (MCT) ketogenic diet have suggested that medium-chain fatty acids (MCFAs) provided in the diet, decanoic acid and octanoic acid, cause specific therapeutic effects independent of glucose reduction, although a role in autophagy has not been investigated. Both autophagy and MCFAs have been widely studied in Dictyostelium, with findings providing important advances in the study of autophagy-related pathologies such as neurodegenerative diseases. Here, we utilize this model to analyze a role for MCFAs in regulating autophagy. We show that treatment with decanoic acid but not octanoic acid induces autophagosome formation and modulates autophagic flux in high glucose conditions. To investigate this effect, decanoic acid, but not octanoic acid, was found to induce the expression of autophagy-inducing proteins (Atg1 and Atg8), providing a mechanism for this effect. Finally, we demonstrate a range of related fatty acid derivatives with seizure control activity, 4BCCA, 4EOA, and Epilim (valproic acid), also function to induce autophagosome formation in this model. Thus, our data suggest that decanoic acid and related compounds may provide a less-restrictive therapeutic approach to activate autophagy.<\/jats:p>","DOI":"10.3390\/cells10112946","type":"journal-article","created":{"date-parts":[[2021,11,1]],"date-time":"2021-11-01T22:21:08Z","timestamp":1635805268000},"page":"2946","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Decanoic Acid Stimulates Autophagy in D. discoideum"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8802-3407","authenticated-orcid":false,"given":"Eleanor C.","family":"Warren","sequence":"first","affiliation":[{"name":"Centre for Biomedical Sciences, Department of Biological Sciences, Royal Holloway University of London, Egham TW20 0EX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavol","family":"Kram\u00e1r","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Sciences, Department of Biological Sciences, Royal Holloway University of London, Egham TW20 0EX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katie","family":"Lloyd-Jones","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Sciences, Department of Biological Sciences, Royal Holloway University of London, Egham TW20 0EX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9826-6020","authenticated-orcid":false,"given":"Robin S. B.","family":"Williams","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Sciences, Department of Biological Sciences, Royal Holloway University of London, Egham TW20 0EX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1007\/s00702-014-1312-1","article-title":"The role of autophagy in epileptogenesis and in epilepsy-induced neuronal alterations","volume":"122","author":"Giorgi","year":"2015","journal-title":"J. Neural. Transm."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"15704","DOI":"10.1523\/JNEUROSCI.2392-12.2012","article-title":"Impaired autophagy in neurons after disinhibition of mammalian target of rapamycin and its contribution to epileptogenesis","volume":"32","author":"McMahon","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"124","DOI":"10.4161\/auto.23323","article-title":"The ULK1 complex: Sensing nutrient signals for autophagy activation","volume":"9","author":"Wong","year":"2013","journal-title":"Autophagy"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2867","DOI":"10.1093\/hmg\/ddq190","article-title":"Laforin, the most common protein mutated in Lafora disease, regulates autophagy","volume":"19","author":"Aguado","year":"2010","journal-title":"Hum. Mol. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.2174\/1567205015666181004143432","article-title":"The Implications of Autophagy in Alzheimer\u2019s Disease","volume":"15","author":"Hamano","year":"2018","journal-title":"Curr. Alzheimer Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1007\/s10571-016-0386-8","article-title":"Autophagy and Alzheimer\u2019s Disease","volume":"37","author":"Li","year":"2017","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_7","first-page":"a009357","article-title":"The role of autophagy in Parkinson\u2019s disease","volume":"2","author":"Mao","year":"2012","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.neulet.2010.04.022","article-title":"Alpha-synuclein nitration and autophagy response are induced in peripheral blood cells from patients with Parkinson disease","volume":"477","author":"Prigione","year":"2010","journal-title":"Neurosci. Lett."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1038\/nature04724","article-title":"Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice","volume":"441","author":"Hara","year":"2006","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.brainres.2017.10.009","article-title":"Ketogenic diet attenuates neuronal injury via autophagy and mitochondrial pathways in pentylenetetrazol-kindled seizures","volume":"1678","author":"Wang","year":"2018","journal-title":"Brain Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.eplepsyres.2015.11.021","article-title":"Ketogenic diet change cPLA2\/clusterin and autophagy related gene expression and correlate with cognitive deficits and hippocampal MFs sprouting following neonatal seizures","volume":"120","author":"Ni","year":"2016","journal-title":"Epilepsy Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e7","DOI":"10.1111\/j.1528-1167.2011.02981.x","article-title":"The ketogenic diet inhibits the mammalian target of rapamycin (mTOR) pathway","volume":"52","author":"McDaniel","year":"2011","journal-title":"Epilepsia"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1203\/01.pdr.0000238244.54610.27","article-title":"Leptin contributes to slower weight gain in juvenile rodents on a ketogenic diet","volume":"60","author":"Thio","year":"2006","journal-title":"Pediatr. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"23813","DOI":"10.1073\/pnas.1912573116","article-title":"Ketone body receptor GPR43 regulates lipid metabolism under ketogenic conditions","volume":"116","author":"Miyamoto","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1007\/s11064-015-1700-4","article-title":"The Ketone Body, \u03b2-Hydroxybutyrate Stimulates the Autophagic Flux and Prevents Neuronal Death Induced by Glucose Deprivation in Cortical Cultured Neurons","volume":"41","author":"Montiel","year":"2016","journal-title":"Neurochem. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1111\/j.1528-1167.2008.01870.x","article-title":"A randomized trial of classical and medium-chain triglyceride ketogenic diets in the treatment of childhood epilepsy","volume":"50","author":"Neal","year":"2009","journal-title":"Epilepsia"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1111\/j.1365-277X.2010.01043.x","article-title":"Efficacy of dietary treatments for epilepsy","volume":"23","author":"Neal","year":"2010","journal-title":"J. Hum. Nutr. Diet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1242\/dmm.008029","article-title":"The antiepileptic drug valproic acid and other medium-chain fatty acids acutely reduce phosphoinositide levels independently of inositol in Dictyostelium","volume":"5","author":"Chang","year":"2012","journal-title":"Dis. Model. Mech."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.neuropharm.2012.11.004","article-title":"Seizure control by ketogenic diet-associated medium chain fatty acids","volume":"69","author":"Chang","year":"2013","journal-title":"Neuropharmacology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1093\/brain\/awv325","article-title":"Seizure control by decanoic acid through direct AMPA receptor inhibition","volume":"139","author":"Chang","year":"2016","journal-title":"Brain"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"dmm035600","DOI":"10.1242\/dmm.035600","article-title":"Diacylglycerol kinase (DGKA) regulates the effect of the epilepsy and bipolar disorder treatment valproic acid in Dictyostelium discoideum","volume":"11","author":"Kelly","year":"2018","journal-title":"Dis. Model. Mech."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/S1474-4422(17)30408-8","article-title":"Mechanisms of action for the medium-chain triglyceride ketogenic diet in neurological and metabolic disorders","volume":"17","author":"Augustin","year":"2018","journal-title":"Lancet Neurol."},{"key":"ref_23","unstructured":"Yelshanskaya, M.V., Singh, A.K., Narangoda, C., Williams, R.S.B., Kurnikova, M.G., and Sobolevsky, A.I. (2020). Structural basis of AMPA receptor inhibition by 4-BCCA. Br. J. Pharmacol., 1\u201317."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1111\/jnc.12646","article-title":"The ketogenic diet component decanoic acid increases mitochondrial citrate synthase and complex I activity in neuronal cells","volume":"129","author":"Hughes","year":"2014","journal-title":"J. Neurochem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1111\/epi.13833","article-title":"Neuronal decanoic acid oxidation is markedly lower than that of octanoic acid: A mechanistic insight into the medium-chain triglyceride ketogenic diet","volume":"58","author":"Khabbush","year":"2017","journal-title":"Epilepsia"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"199","DOI":"10.3389\/fncel.2018.00199","article-title":"All You Need Is Fats-for Seizure Control: Using Amoeba to Advance Epilepsy Research","volume":"12","author":"Warren","year":"2018","journal-title":"Front. Cell. Neurosci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1111\/bph.15351","article-title":"Phytocannabinoid-dependent mTORC1 regulation is dependent upon inositol polyphosphate multikinase activity","volume":"178","author":"Warren","year":"2021","journal-title":"Br. J. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1111\/bph.14892","article-title":"A new mechanism for Cannabidiol in regulating the one-carbon cycle and methionine levels in Dictyostelium and in mammalian epilepsy models","volume":"177","author":"Perry","year":"2020","journal-title":"Br. J. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1128\/EC.00104-06","article-title":"Attenuation of phospholipid signaling provides a novel mechanism for the action of valproic acid","volume":"6","author":"Xu","year":"2007","journal-title":"Eukaryot. Cell."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1016\/j.ejcb.2006.04.013","article-title":"The neuroprotective agent, valproic acid, regulates the mitogen-activated protein kinase pathway through modulation of protein kinase A signalling in Dictyostelium discoideum","volume":"85","author":"Boeckeler","year":"2006","journal-title":"Eur. J. Cell. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"17636","DOI":"10.1074\/jbc.M212467200","article-title":"Macroautophagy is required for multicellular development of the social amoeba Dictyostelium discoideum","volume":"278","author":"Otto","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Cardenal-Munoz, E., Arafah, S., Lopez-Jimenez, A.T., Kicka, S., Falaise, A., Bach, F., Schaad, O., King, J.S., Hagedorn, M., and Soldati, T. (2017). Mycobacterium marinum antagonistically induces an autophagic response while repressing the autophagic flux in a TORC1- and ESX-1-dependent manner. PLoS Pathog., 13.","DOI":"10.1371\/journal.ppat.1006344"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"737071","DOI":"10.3389\/fcell.2021.737071","article-title":"The WIPI Gene Family and Neurodegenerative Diseases: Insights From Yeast and Dictyostelium Models","volume":"9","author":"Vincent","year":"2021","journal-title":"Front Cell Dev Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1080\/15548627.2016.1226737","article-title":"Autophagy in Dictyostelium: Mechanisms, regulation and disease in a simple biomedical model","volume":"13","author":"Mesquita","year":"2017","journal-title":"Autophagy"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.ejcb.2017.03.014","article-title":"The two Dictyostelium discoideum autophagy 8 proteins have distinct autophagic functions","volume":"96","author":"Messling","year":"2017","journal-title":"Eur. J. Cell Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1387\/ijdb.190186LE","article-title":"Dictyostelium discoideum and autophagy\u2014A perfect pair","volume":"63","author":"Fischer","year":"2019","journal-title":"Int. J. Dev. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1111\/tra.12210","article-title":"Vmp1 regulates PtdIns3P signaling during autophagosome formation in Dictyostelium discoideum","volume":"15","author":"King","year":"2014","journal-title":"Traffic"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1080\/15548627.2015.1034413","article-title":"TipC and the chorea-acanthocytosis protein VPS13A regulate autophagy in Dictyostelium and human HeLa cells","volume":"11","author":"Calvo","year":"2015","journal-title":"Autophagy"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"100","DOI":"10.4161\/auto.6.1.10697","article-title":"Autophagy dysfunction and ubiquitin-positive protein aggregates in Dictyostelium cells lacking Vmp1","volume":"6","author":"Escalante","year":"2010","journal-title":"Autophagy"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"44","DOI":"10.4161\/auto.5.1.7228","article-title":"Autophagy contributes to degradation of Hirano bodies","volume":"5","author":"Kim","year":"2009","journal-title":"Autophagy"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.ejcb.2009.02.185","article-title":"Targeting the actin-binding protein VASP to late endosomes induces the formation of giant actin aggregates","volume":"88","author":"Schmauch","year":"2009","journal-title":"Eur. J. Cell. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1490","DOI":"10.4161\/auto.7.12.17924","article-title":"The induction of autophagy by mechanical stress","volume":"7","author":"King","year":"2011","journal-title":"Autophagy"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1007\/978-1-62703-302-2_26","article-title":"Monitoring autophagy in Dictyostelium","volume":"983","author":"Mesquita","year":"2013","journal-title":"Methods Mol. Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1080\/15548627.2019.1586245","article-title":"Gamma secretase orthologs are required for lysosomal activity and autophagic degradation in Dictyostelium discoideum, independent of PSEN (presenilin) proteolytic function","volume":"15","author":"Sharma","year":"2019","journal-title":"Autophagy"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Dominguez-Martin, E., Cardenal-Munoz, E., King, J.S., Soldati, T., Coria, R., and Escalante, R. (2017). Methods to Monitor and Quantify Autophagy in the Social Amoeba Dictyostelium discoideum. Cells, 6.","DOI":"10.3390\/cells6030018"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.4161\/auto.7.9.16629","article-title":"A proteolytic cleavage assay to monitor autophagy in Dictyostelium discoideum","volume":"7","author":"Mesquita","year":"2011","journal-title":"Autophagy"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"794","DOI":"10.4161\/auto.6.6.12348","article-title":"Quantification of nonselective bulk autophagy in S. cerevisiae using Pgk1-GFP","volume":"6","author":"Welter","year":"2010","journal-title":"Autophagy"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1007\/978-1-60761-198-1_17","article-title":"Assays for chemotaxis and chemoattractant-stimulated TorC2 activation and PKB substrate phosphorylation in Dictyostelium","volume":"571","author":"Kamimura","year":"2009","journal-title":"Methods Mol. Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"23617","DOI":"10.1073\/pnas.2008980117","article-title":"Decanoic acid inhibits mTORC1 activity independent of glucose and insulin signaling","volume":"117","author":"Warren","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1111\/febs.15127","article-title":"Phosphoinositides in autophagy: Current roles and future insights","volume":"287","author":"Palamiuc","year":"2020","journal-title":"FEBS J."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1007\/s12272-016-0777-x","article-title":"The roles of phosphoinositides in mammalian autophagy","volume":"39","author":"Jang","year":"2016","journal-title":"Arch. Pharm. Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"5019","DOI":"10.1091\/mbc.e03-08-0566","article-title":"Uniform cAMP stimulation of Dictyostelium cells induces localized patches of signal transduction and pseudopodia","volume":"14","author":"Postma","year":"2003","journal-title":"Mol. Biol. Cell."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.yexcr.2012.11.014","article-title":"Protein kinase B\/Akt1 inhibits autophagy by down-regulating UVRAG expression","volume":"319","author":"Yang","year":"2013","journal-title":"Exp. Cell. Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"a011189","DOI":"10.1101\/cshperspect.a011189","article-title":"PI3K-PKB\/Akt pathway","volume":"4","author":"Hemmings","year":"2012","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"jcs236505","DOI":"10.1242\/jcs.236505","article-title":"Two conserved glycine residues in mammalian and Dictyostelium Rictor are required for mTORC2 activity and integrity","volume":"132","author":"Pergolizzi","year":"2019","journal-title":"J. Cell. Sci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1034","DOI":"10.1016\/j.cub.2008.06.068","article-title":"PIP(3)-Independent Activation of TorC2 and PKB at the Cell\u2019s Leading Edge Mediates Chemotaxis","volume":"18","author":"Kamimura","year":"2008","journal-title":"Curr. Biol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3691","DOI":"10.1038\/emboj.2012.225","article-title":"Binding of the Atg1\/ULK1 kinase to the ubiquitin-like protein Atg8 regulates autophagy","volume":"31","author":"Kraft","year":"2012","journal-title":"EMBO J."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"3083","DOI":"10.1007\/s00018-015-1917-z","article-title":"Atg1 family kinases in autophagy initiation","volume":"72","author":"Noda","year":"2015","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Karow, M., Fischer, S., Messling, S., Konertz, R., Riehl, J., Xiong, Q., Rijal, R., Wagle, P., Clemen, C.S., and Eichinger, L. (2020). Functional Characterisation of the Autophagy ATG12~5\/16 Complex in Dictyostelium discoideum. Cells, 9.","DOI":"10.3390\/cells9051179"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1083\/jcb.147.2.435","article-title":"Formation process of autophagosome is traced with Apg8\/Aut7p in yeast","volume":"147","author":"Kirisako","year":"1999","journal-title":"J. Cell. Biol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1124\/jpet.114.218768","article-title":"Seizure control by derivatives of medium chain fatty acids associated with the ketogenic diet show novel branching-point structure for enhanced potency","volume":"352","author":"Chang","year":"2015","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1038\/cr.2013.161","article-title":"Autophagy and human diseases","volume":"24","author":"Jiang","year":"2014","journal-title":"Cell. Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"e5","DOI":"10.1111\/epi.13957","article-title":"Severe infantile onset developmental and epileptic encephalopathy caused by mutations in autophagy gene WDR45","volume":"59","author":"Carvill","year":"2018","journal-title":"Epilepsia"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1387\/ijdb.190228rw","article-title":"Dictyostelium discoideum as a pharmacological model system to study the mechanisms of medicinal drugs and natural products","volume":"63","author":"Schaf","year":"2019","journal-title":"Int. J. Dev. Biol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"e20200014","DOI":"10.1590\/1678-4685-gmb-2020-0014","article-title":"The paradox of autophagy in Tuberous Sclerosis Complex","volume":"44","author":"Reis","year":"2021","journal-title":"Genet. Mol. Biol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"7988","DOI":"10.1523\/JNEUROSCI.0777-14.2014","article-title":"Genetic reduction of mammalian target of rapamycin ameliorates Alzheimer\u2019s disease-like cognitive and pathological deficits by restoring hippocampal gene expression signature","volume":"34","author":"Caccamo","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1007\/s12031-015-0703-6","article-title":"Cannabidiol Post-Treatment Alleviates Rat Epileptic-Related Behaviors and Activates Hippocampal Cell Autophagy Pathway Along with Antioxidant Defense in Chronic Phase of Pilocarpine-Induced Seizure","volume":"58","author":"Hosseinzadeh","year":"2016","journal-title":"J. Mol. Neurosci."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Limanaqi, F., Biagioni, F., Busceti, C.L., Fabrizi, C., Frati, A., and Fornai, F. (2020). mTOR-Related Cell-Clearing Systems in Epileptic Seizures, an Update. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21051642"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.yebeh.2014.02.026","article-title":"Rationale for using intermittent calorie restriction as a dietary treatment for drug resistant epilepsy","volume":"33","author":"Yuen","year":"2014","journal-title":"Epilepsy Behav."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s40263-018-0497-5","article-title":"Activating Autophagy as a Therapeutic Strategy for Parkinson\u2019s Disease","volume":"32","author":"Fowler","year":"2018","journal-title":"CNS Drugs"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1038\/ng1362","article-title":"Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease","volume":"36","author":"Ravikumar","year":"2004","journal-title":"Nat. Genet."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Schoeler, N.E., Orford, M., Vivekananda, U., Simpson, Z., Van de Bor, B., Smith, H., Balestrini, S., Rutherford, T., Brennan, E., and McKenna, J. (2021). Vita\u00ae: A feasibility study of a blend of medium chain triglycerides to manage drug-resistant epilepsy. Brain Commun., fcab160. in press.","DOI":"10.1093\/braincomms\/fcab160"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1016\/j.jalz.2018.12.017","article-title":"A ketogenic drink improves brain energy and some measures of cognition in mild cognitive impairment","volume":"15","author":"Fortier","year":"2019","journal-title":"Alzheimers Dement."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"101001","DOI":"10.1016\/j.arr.2019.101001","article-title":"Medium Chain Triglycerides induce mild ketosis and may improve cognition in Alzheimer\u2019s disease. A systematic review and meta-analysis of human studies","volume":"58","author":"Avgerinos","year":"2020","journal-title":"Ageing Res. Rev."},{"key":"ref_75","first-page":"1399","article-title":"Increasing Dietary Medium-Chain Fatty Acid Ratio Mitigates High-fat Diet-Induced Non-Alcoholic Steatohepatitis by Regulating Autophagy","volume":"7","author":"Wang","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"42534","DOI":"10.1074\/jbc.M111.242412","article-title":"Fatty acids suppress autophagic turnover in \u03b2-cells","volume":"286","author":"Las","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1124\/jpet.111.184341","article-title":"Differential roles of unsaturated and saturated fatty acids on autophagy and apoptosis in hepatocytes","volume":"339","author":"Mei","year":"2011","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.ebiom.2018.03.028","article-title":"Trans-Fats Inhibit Autophagy Induced by Saturated Fatty Acids","volume":"30","author":"Sauvat","year":"2018","journal-title":"EBioMedicine"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Martino, L., Masini, M., Novelli, M., Beffy, P., Bugliani, M., Marselli, L., Masiello, P., Marchetti, P., and De Tata, V. (2012). Palmitate activates autophagy in INS-1E \u03b2-cells and in isolated rat and human pancreatic islets. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0036188"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1080\/19768354.2019.1696407","article-title":"Palmitate-induced autophagy liberates monounsaturated fatty acids and increases Agrp expression in hypothalamic cells","volume":"23","author":"Park","year":"2019","journal-title":"Anim. Cells. Syst."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1007\/s00441-009-0926-3","article-title":"Oleate and linoleate stimulate degradation of \u03b2-casein in prolactin-treated HC11 mouse mammary epithelial cells","volume":"340","author":"Pauloin","year":"2010","journal-title":"Cell Tissue Res."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.mehy.2009.07.022","article-title":"Activation of the AMP activated protein kinase by short-chain fatty acids is the main mechanism underlying the beneficial effect of a high fiber diet on the metabolic syndrome","volume":"74","author":"Hu","year":"2010","journal-title":"Med. Hypotheses"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1872","DOI":"10.3945\/jn.113.179549","article-title":"Short-chain fatty acids activate AMP-activated protein kinase and ameliorate ethanol-induced intestinal barrier dysfunction in Caco-2 cell monolayers","volume":"143","author":"Elamin","year":"2013","journal-title":"J. Nutr."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.nbd.2013.10.017","article-title":"Seizure-induced reduction in PIP3 levels contributes to seizure-activity and is rescued by valproic acid","volume":"62","author":"Chang","year":"2014","journal-title":"Neurobiol. Dis."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1007\/s40263-014-0223-x","article-title":"mTOR inhibition in epilepsy: Rationale and clinical perspectives","volume":"29","author":"Ostendorf","year":"2015","journal-title":"CNS Drugs"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/s40035-017-0077-5","article-title":"Protein misfolding in neurodegenerative diseases: Implications and strategies","volume":"6","author":"Sweeney","year":"2017","journal-title":"Transl. Neurodegener."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/j.cmet.2017.08.005","article-title":"A Ketogenic Diet Extends Longevity and Healthspan in Adult Mice","volume":"26","author":"Roberts","year":"2017","journal-title":"Cell Metab."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Jaiswal, P., and Kimmel, A.R. (2019). mTORC1\/AMPK responses define a core gene set for developmental cell fate switching. 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