title: Targeting surface voids to counter membrane disorders in lipointoxication-related diseases.
abstract: Saturated fatty acids (SFA), which are abundant in the so-called western diet, have been shown to efficiently incorporate within membrane phospholipids and therefore impact on organelle integrity and function in many cell types. In the present study, we have developed a yeast-based two-step assay and a virtual screening strategy to identify new drugs able to counter SFA-mediated lipointoxication. The compounds identified here were effective in relieving lipointoxication in mammalian β-cells, one of the main targets of SFA toxicity in humans. In vitro reconstitutions and molecular dynamics simulations on bilayers revealed that these molecules, albeit according to different mechanisms, can generate voids at the membrane surface. The resulting surface defects correlate with the recruitment of loose lipid packing or void-sensing proteins required for vesicular budding, a central cellular process that is precluded under SFA accumulation. Taken together, the results presented here point at modulation of surface voids as a central parameter to consider in order to counter the impacts of SFA on cell function.
authors.affiliation: Laboratoire Signalisation et Transports Ioniques Membranaires (STIM), CNRS ERL 7368, Université de Poitiers, 1, rue Georges Bonnet, Poitiers Cedex 9 86073, France Société d'Accélération du Transfert de Technologie (SATT) Grand Centre, 8 rue Pablo Picasso, Clermont-Ferrand 63000, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Ferru-Clément
authors.affiliation: Laboratoire Signalisation et Transports Ioniques Membranaires (STIM), CNRS ERL 7368, Université de Poitiers, 1, rue Georges Bonnet, Poitiers Cedex 9 86073, France.
authors.forename: Miroslava
authors.initials: M
authors.lastname: Spanova
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter EX2 5DW, UK.
authors.forename: Shalinee
authors.initials: S
authors.lastname: Dhayal
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter EX2 5DW, UK.
authors.forename: Noel G
authors.initials: NG
authors.lastname: Morgan
authors.affiliation: Société d'Accélération du Transfert de Technologie (SATT) Grand Centre, 8 rue Pablo Picasso, Clermont-Ferrand 63000, France.
authors.forename: Reynald
authors.initials: R
authors.lastname: Hélye
authors.affiliation: Laboratoire Signalisation et Transports Ioniques Membranaires (STIM), CNRS ERL 7368, Université de Poitiers, 1, rue Georges Bonnet, Poitiers Cedex 9 86073, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Becq
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, CNRS UMR 7275, Université de Nice Sofia-Antipolis, 660 route des Lucioles, Valbonne 06560, France.
authors.forename: Hisaaki
authors.initials: H
authors.lastname: Hirose
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, CNRS UMR 7275, Université de Nice Sofia-Antipolis, 660 route des Lucioles, Valbonne 06560, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Antonny
authors.affiliation: Dynamique des membranes et trafic intracellulaire, Institut Jacques Monod, CNRS UMR 7592, Université Paris Diderot, Sorbonne Paris Cité, 15 rue Hélène Brion, Paris 75013, France.
authors.forename: Lydie
authors.initials: L
authors.lastname: Vamparys
authors.affiliation: Dynamique des membranes et trafic intracellulaire, Institut Jacques Monod, CNRS UMR 7592, Université Paris Diderot, Sorbonne Paris Cité, 15 rue Hélène Brion, Paris 75013, France.
authors.forename: Patrick F J
authors.initials: PF
authors.lastname: Fuchs
authors.affiliation: Laboratoire Signalisation et Transports Ioniques Membranaires (STIM), CNRS ERL 7368, Université de Poitiers, 1, rue Georges Bonnet, Poitiers Cedex 9 86073, France thierry.ferreira@univ-poitiers.fr.
authors.forename: Thierry
authors.identifier: 0000-0002-7727-9105
authors.initials: T
authors.lastname: Ferreira
mesh_terms: D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D004075:Diglycerides / Q000494:pharmacology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D008055:Lipids / Q000633:toxicity*; D008246:Lysophospholipids / Q000494:pharmacology; D055442:Metabolome / Q000187:drug effects; D055432:Metabolomics; D010597:Pharmacogenetics; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000378:metabolism*; D055571:Secretory Pathway / Q000187:drug effects; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics; D014584:User-Computer Interface
chemical_list: D004075:Diglycerides; D008055:Lipids; D008246:Lysophospholipids; C038237:1-oleoyl-2-acetylglycerol; C032881:lysophosphatidic acid
keywords: Early secretory pathway; Lipointoxication; Membrane interfacial surface voids; Type 2 diabetes