title: Saturated fatty acids alter the late secretory pathway by modulating membrane properties.
abstract: Saturated fatty acids (SFA) have been reported to alter organelle integrity and function in many cell types, including muscle and pancreatic β-cells, adipocytes, hepatocytes and cardiomyocytes. SFA accumulation results in increased amounts of ceramides/sphingolipids and saturated phospholipids (PL). In this study, using a yeast-based model that recapitulates most of the trademarks of SFA-induced lipotoxicity in mammalian cells, we demonstrate that these lipid species act at different levels of the secretory pathway. Ceramides mostly appear to modulate the induction of the unfolded protein response and the transcription of nutrient transporters destined to the cell surface. On the other hand, saturated PL, by altering membrane properties, directly impact vesicular budding at later steps in the secretory pathway, i.e. at the trans-Golgi Network level. They appear to do so by increasing lipid order within intracellular membranes which, in turn, alters the recruitment of loose lipid packing-sensing proteins, required for optimal budding, to nascent vesicles. We propose that this latter general mechanism could account for the well-documented deleterious impacts of fatty acids on the last steps of the secretory pathway in several cell types.
authors.affiliation: Université de Poitiers, Institut de Physiologie et de Biologie Cellulaires, FRE CNRS 3511, Pôle Biologie-Santé, 1, Rue Georges BONNET, BP 633, 86022, Poitiers Cedex, France.
authors.forename: Laurie-Anne
authors.initials: LA
authors.lastname: Payet
authors.forename: Ludovic
authors.initials: L
authors.lastname: Pineau
authors.forename: Ellen C R
authors.initials: EC
authors.lastname: Snyder
authors.forename: Jenny
authors.initials: J
authors.lastname: Colas
authors.forename: Ahmed
authors.initials: A
authors.lastname: Moussa
authors.forename: Brigitte
authors.initials: B
authors.lastname: Vannier
authors.forename: Joelle
authors.initials: J
authors.lastname: Bigay
authors.forename: Jonathan
authors.initials: J
authors.lastname: Clarhaut
authors.forename: Frédéric
authors.initials: F
authors.lastname: Becq
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Berjeaud
authors.forename: Clarisse
authors.initials: C
authors.lastname: Vandebrouck
authors.forename: Thierry
authors.initials: T
authors.lastname: Ferreira
mesh_terms: D002462:Cell Membrane / Q000378:metabolism*; D002518:Ceramides / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D055571:Secretory Pathway; D022161:Transport Vesicles / Q000378:metabolism; D056811:Unfolded Protein Response; D021601:trans-Golgi Network / Q000378:metabolism
chemical_list: D002518:Ceramides; D005227:Fatty Acids; D010743:Phospholipids
keywords: Arf-GAP1; loose lipid packing; protein trafficking; trans-Golgi network; type 2 diabetes; vesicular budding