title: Cystic fibrosis bronchial epithelial cells are lipointoxicated by membrane palmitate accumulation.
abstract: The F508del-CFTR mutation, responsible for Cystic Fibrosis (CF), leads to the retention of the protein in the endoplasmic reticulum (ER). The mistrafficking of this mutant form can be corrected by pharmacological chaperones, but these molecules showed limitations in clinical trials. We therefore hypothesized that important factors in CF patients may have not been considered in the in vitro assays. CF has also been associated with an altered lipid homeostasis, i. e. a decrease in polyunsaturated fatty acid levels in plasma and tissues. However, the precise fatty acyl content of membrane phospholipids from human CF bronchial epithelial cells had not been studied to date. Since the saturation level of phospholipids can modulate crucial membrane properties, with potential impacts on membrane protein folding/trafficking, we analyzed this parameter for freshly isolated bronchial epithelial cells from CF patients. Interestingly, we could show that Palmitate, a saturated fatty acid, accumulates within Phosphatidylcholine (PC) in CF freshly isolated cells, in a process that could result from hypoxia. The observed PC pattern can be recapitulated in the CFBE41o(-) cell line by incubation with 100 µM Palmitate. At this concentration, Palmitate induces an ER stress, impacts calcium homeostasis and leads to a decrease in the activity of the corrected F508del-CFTR. Overall, these data suggest that bronchial epithelial cells are lipointoxicated by hypoxia-related Palmitate accumulation in CF patients. We propose that this phenomenon could be an important bottleneck for F508del-CFTR trafficking correction by pharmacological agents in clinical trials.
authors.affiliation: Signalisation et Transports Ioniques Membranaires, ERL CNRS 7368, Université de Poitiers, Poitiers, France.
authors.forename: Laurie-Anne
authors.initials: LA
authors.lastname: Payet
authors.affiliation: Ecologie et Biologie des Interactions, UMR CNRS 7267, Université de Poitiers, Poitiers, France.
authors.forename: Linette
authors.initials: L
authors.lastname: Kadri
authors.affiliation: Service de Biochimie, CHU Poitiers, Poitiers, France ; Inserm U1082, Poitiers, France ; Faculté de Médecine et de Pharmacie Université de Poitiers, Poitiers, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Giraud
authors.affiliation: Signalisation et Transports Ioniques Membranaires, ERL CNRS 7368, Université de Poitiers, Poitiers, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Norez
authors.affiliation: Ecologie et Biologie des Interactions, UMR CNRS 7267, Université de Poitiers, Poitiers, France.
authors.forename: Jean Marc
authors.initials: JM
authors.lastname: Berjeaud
authors.affiliation: Service de Chirurgie Cardiothoracique, CHU Poitiers, Poitiers, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Jayle
authors.affiliation: Signalisation et Transports Ioniques Membranaires, ERL CNRS 7368, Université de Poitiers, Poitiers, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Mirval
authors.affiliation: Signalisation et Transports Ioniques Membranaires, ERL CNRS 7368, Université de Poitiers, Poitiers, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Becq
authors.affiliation: Signalisation et Transports Ioniques Membranaires, ERL CNRS 7368, Université de Poitiers, Poitiers, France.
authors.forename: Clarisse
authors.initials: C
authors.lastname: Vandebrouck
authors.affiliation: Signalisation et Transports Ioniques Membranaires, ERL CNRS 7368, Université de Poitiers, Poitiers, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Ferreira
mesh_terms: D000328:Adult; D000368:Aged; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D019308:Palmitic Acid / Q000302:isolation & purification / Q000378:metabolism / Q000633:toxicity*; D021381:Protein Transport / Q000187:drug effects; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000473:pathology
chemical_list: C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D019308:Palmitic Acid