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Études des propriétés fonctionnelles et du rôle de la protéine membranaire SLC5A8

Laurent Suissa 1
1 TIRO - UMR E4320 - Transporteurs en Imagerie et Radiothérapie en Oncologie
SHFJ - Service Hospitalier Frédéric Joliot, TIRO-MATOs - UMR E4320 : UMR E4320
Abstract : The functional properties of the SLC5A8 membrane protein and its physiological role have been studied in vitro and in vivo using slc5a8-/- mice. In vitro, analysis of metabolite uptake by LC-MS with slc5a8 transfected HEK cells to study sodium-dependent transport of monocarboxylates, in particular pyruvate but also ketone bodies. Using a metabolomic approach, we showed that SLC5A8-mediated pyruvate uptake fuels the Krebs cycle and has an inhibitory effect on the glycolytic enzyme, GAPDH. Bromopyruvate, the halogen derivative of pyruvate, is a known antitumour agent targeting GAPDH and has a similar effect. We propose that the tumour suppressor function reported for SLC5A8 in the literature is associated with an "anti-Warburg" effect. In vivo, aged slc5a8-/- mice showed diffuse intramyelinic oedema without demyelination. This indicated a hydro-ionic disorder in the periaxonal space due to chronic energy deficiency. While expression of SLC5A8 was confirmed in renal tubular cells, the expression of the protein was not detected in brain suggesting a renal origin of the described leukoencephalopathy. Slc5a8-/- mice showed strong urinary loss of ketone bodies leading to cerebral insufficiency of β-hydroxybutyrate. This ketone is an essential energy source for the brain, in particular when carbohydrate metabolism is dysfunctionning, like in the case of insulin resistance that was found in aged slc5a8-/- mice. This study highlights the major role of ketone bodies in neuroenergetics.
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Laurent Suissa. Études des propriétés fonctionnelles et du rôle de la protéine membranaire SLC5A8. Biochimie, Biologie Moléculaire. Université Côte d'Azur, 2018. Français. ⟨NNT : 2018AZUR4034⟩. ⟨tel-01907742⟩

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