Decanoic acid inhibits mTORC1 activity independent of glucose and insulin signaling.

Autor:	Warren EC; Centre for Biomedical Sciences, Department of Biological Sciences, Royal Holloway University of London, Egham TW20 0EX, United Kingdom., Dooves S; Department of Child and Youth Psychiatry, Amsterdam Universitair Medische Centra, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands., Lugarà E; Clinical and Experimental Epilepsy UCL, Queen Square Institute of Neurology, University College London, London WC1N 3BG, United Kingdom., Damstra-Oddy J; Centre for Biomedical Sciences, Department of Biological Sciences, Royal Holloway University of London, Egham TW20 0EX, United Kingdom., Schaf J; Centre for Biomedical Sciences, Department of Biological Sciences, Royal Holloway University of London, Egham TW20 0EX, United Kingdom., Heine VM; Department of Child and Youth Psychiatry, Amsterdam Universitair Medische Centra, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands.; Department of Complex Trait Genetics, Centre for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands., Walker MC; Clinical and Experimental Epilepsy UCL, Queen Square Institute of Neurology, University College London, London WC1N 3BG, United Kingdom., Williams RSB; Centre for Biomedical Sciences, Department of Biological Sciences, Royal Holloway University of London, Egham TW20 0EX, United Kingdom; robin.williams@rhul.ac.uk.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Sep 22; Vol. 117 (38), pp. 23617-23625. Date of Electronic Publication: 2020 Sep 02.
DOI:	10.1073/pnas.2008980117
Abstrakt:	Low-glucose and -insulin conditions, associated with ketogenic diets, can reduce the activity of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway, potentially leading to a range of positive medical and health-related effects. Here, we determined whether mTORC1 signaling is also a target for decanoic acid, a key component of the medium-chain triglyceride (MCT) ketogenic diet. Using a tractable model system, Dictyostelium , we show that decanoic acid can decrease mTORC1 activity, under conditions of constant glucose and in the absence of insulin, measured by phosphorylation of eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1). We determine that this effect of decanoic acid is dependent on a ubiquitin regulatory X domain-containing protein, mediating inhibition of a conserved Dictyostelium AAA ATPase, p97, a homolog of the human transitional endoplasmic reticulum ATPase (VCP/p97) protein. We then demonstrate that decanoic acid decreases mTORC1 activity in the absence of insulin and under high-glucose conditions in ex vivo rat hippocampus and in tuberous sclerosis complex (TSC) patient-derived astrocytes. Our data therefore indicate that dietary decanoic acid may provide a new therapeutic approach to down-regulate mTORC1 signaling. Competing Interests: Competing interest statement: M.C.W. and R.S.B.W. are named inventors on related patents WO2019002435A1, WO2012069790A1, WO2016038379A1, and WO2018189113. (Copyright © 2020 the Author(s). Published by PNAS.)
Databáze:	MEDLINE
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