title: Endoplasmic Reticulum Stress Links Oxidative Stress to Impaired Pancreatic Beta-Cell Function Caused by Human Oxidized LDL.
abstract: Elevated plasma concentration of the pro-atherogenic oxidized low density lipoprotein cholesterol (LDL) triggers adverse effects in pancreatic beta-cells and is associated with type 2 diabetes. Here, we investigated whether the endoplasmic reticulum (ER) stress is a key player coupling oxidative stress to beta-cell dysfunction and death elicited by human oxidized LDL. We found that human oxidized LDL activates ER stress as evidenced by the activation of the inositol requiring 1α, and the elevated expression of both DDIT3 (also called CHOP) and DNAJC3 (also called P58IPK) ER stress markers in isolated human islets and the mouse insulin secreting MIN6 cells. Silencing of Chop and inhibition of ER stress markers by the chemical chaperone phenyl butyric acid (PBA) prevented cell death caused by oxidized LDL. Finally, we found that oxidative stress accounts for activation of ER stress markers induced by oxidized LDL. Induction of Chop/CHOP and p58IPK/P58IPK by oxidized LDL was mimicked by hydrogen peroxide and was blocked by co-treatment with the N-acetylcystein antioxidant. As a conclusion, the harmful effects of oxidized LDL in beta-cells requires ER stress activation in a manner that involves oxidative stress. This mechanism may account for impaired beta-cell function in diabetes and can be reversed by antioxidant treatment.
authors.affiliation: Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199 - EGID, Lille, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Plaisance
authors.affiliation: Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199 - EGID, Lille, France.|Service of Internal Medicine, Centre Hospitalier Universitaire Vaudois and Lausanne University, Lausanne, Switzerland.
authors.forename: Saška
authors.initials: S
authors.lastname: Brajkovic
authors.affiliation: Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199 - EGID, Lille, France.
authors.forename: Mathie
authors.initials: M
authors.lastname: Tenenbaum
authors.affiliation: Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199 - EGID, Lille, France.|Service of Internal Medicine, Centre Hospitalier Universitaire Vaudois and Lausanne University, Lausanne, Switzerland.
authors.forename: Dimitri
authors.initials: D
authors.lastname: Favre
authors.affiliation: Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199 - EGID, Lille, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Ezanno
authors.affiliation: Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199 - EGID, Lille, France.|Department of Genomic of Common Disease, Imperial College London, London, United Kingdom.
authors.forename: Amélie
authors.initials: A
authors.lastname: Bonnefond
authors.affiliation: Univ. Lille, Inserm, CHU Lille, U1190 - EGID, Lille, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Bonner
authors.affiliation: Univ. Lille, Inserm, CHU Lille, U1190 - EGID, Lille, France.
authors.forename: Valéry
authors.initials: V
authors.lastname: Gmyr
authors.affiliation: Univ. Lille, Inserm, CHU Lille, U1190 - EGID, Lille, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Kerr-Conte
authors.affiliation: Department of Stem Cells, Andalusian Center for Molecular Biology and Regenerative Medicine, Seville, Spain.
authors.forename: Benoit R
authors.initials: BR
authors.lastname: Gauthier
authors.affiliation: Department of Physiology, Lausanne University, Lausanne, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Widmann
authors.affiliation: Service of Internal Medicine, Centre Hospitalier Universitaire Vaudois and Lausanne University, Lausanne, Switzerland.
authors.forename: Gérard
authors.initials: G
authors.lastname: Waeber
authors.affiliation: Univ. Lille, Inserm, CHU Lille, U1190 - EGID, Lille, France.
authors.forename: François
authors.initials: F
authors.lastname: Pattou
authors.affiliation: Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199 - EGID, Lille, France.|Department of Genomic of Common Disease, Imperial College London, London, United Kingdom.
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
authors.affiliation: Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199 - EGID, Lille, France.|Department of Genomic of Common Disease, Imperial College London, London, United Kingdom.
authors.forename: Amar
authors.initials: A
authors.lastname: Abderrahmani
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage; D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D059865:Endoplasmic Reticulum Stress; D004722:Endoribonucleases / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000008:administration & dosage; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008077:Lipoproteins, LDL / Q000502:physiology*; D051379:Mice; D018384:Oxidative Stress; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism
chemical_list: C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D000975:Antioxidants; D015415:Biomarkers; D007328:Insulin; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D006861:Hydrogen Peroxide; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; D000111:Acetylcysteine