title: Glucolipotoxicity impairs ceramide flow from the endoplasmic reticulum to the Golgi apparatus in INS-1 β-cells.
abstract: Accumulating evidence suggests that glucolipotoxicity, arising from the combined actions of elevated glucose and free fatty acid levels, acts as a key pathogenic component in type II diabetes, contributing to β-cell dysfunction and death. Endoplasmic reticulum (ER) stress is among the molecular pathways and regulators involved in these negative effects, and ceramide accumulation due to glucolipotoxicity can be associated with the induction of ER stress. Increased levels of ceramide in ER may be due to enhanced ceramide biosynthesis and/or decreased ceramide utilization. Here, we studied the effect of glucolipotoxic conditions on ceramide traffic in INS-1 cells in order to gain insights into the molecular mechanism(s) of glucolipotoxicity. We showed that glucolipotoxicity inhibited ceramide utilization for complex sphingolipid biosynthesis, thereby reducing the flow of ceramide from the ER to Golgi. Glucolipotoxicity impaired both vesicular- and CERT-mediated ceramide transport through (1) the decreasing of phospho-Akt levels which in turn possibly inhibits vesicular traffic, and (2) the reducing of the amount of active CERT mainly due to a lower protein levels and increased protein phosphorylation to prevent its localization to the Golgi. In conclusion, our findings provide evidence that glucolipotoxicity-induced ceramide overload in the ER, arising from a defect in ceramide trafficking may be a mechanism that contributes to dysfunction and/or death of β-cells exposed to glucolipotoxicity.
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, Università di Milano, LITA Segrate, Milano, Italy.
authors.forename: Enida
authors.initials: E
authors.lastname: Gjoni
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, Università di Milano, LITA Segrate, Milano, Italy.
authors.forename: Loredana
authors.initials: L
authors.lastname: Brioschi
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, Università di Milano, LITA Segrate, Milano, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Cinque
authors.affiliation: Unité Biologie Fonctionnelle et Adaptative -UMR CNRS 8251, Université PARIS- DIDEROT (7), Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Coant
authors.affiliation: School of Biology and Environmental Science and UCD Earth Institute, University College Dublin, Belfield, Ireland.
authors.forename: M Nurul
authors.initials: MN
authors.lastname: Islam
authors.affiliation: School of Biology and Environmental Science and UCD Earth Institute, University College Dublin, Belfield, Ireland.
authors.forename: Carl K-Y
authors.initials: CK
authors.lastname: Ng
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, CNR Institute of Neuroscience, Universita' di Milano, Milano, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Verderio
authors.affiliation: Unité Biologie Fonctionnelle et Adaptative -UMR CNRS 8251, Université PARIS- DIDEROT (7), Paris, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Magnan
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, Università di Milano, LITA Segrate, Milano, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Riboni
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, Università di Milano, LITA Segrate, Milano, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Viani
authors.affiliation: Unité Biologie Fonctionnelle et Adaptative -UMR CNRS 8251, Université PARIS- DIDEROT (7), Paris, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Le Stunff
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, Università di Milano, LITA Segrate, Milano, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Giussani
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival; D002518:Ceramides / Q000737:chemistry*; D003920:Diabetes Mellitus / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D005947:Glucose / Q000737:chemistry*; D006056:Golgi Apparatus / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000166:cytology*; D007340:Insulinoma / Q000378:metabolism; D019308:Palmitic Acid / Q000737:chemistry; D010766:Phosphorylation; D034622:RNA Interference; D051381:Rats; D013109:Sphingomyelins / Q000737:chemistry; D013110:Sphingosine / Q000737:chemistry
chemical_list: D002518:Ceramides; D013109:Sphingomyelins; D019308:Palmitic Acid; D005947:Glucose; D013110:Sphingosine