title: The class I histone deacetylase inhibitor MS-275 prevents pancreatic beta cell death induced by palmitate.
abstract: Elevation of the dietary saturated fatty acid palmitate contributes to the reduction of functional beta cell mass in the pathogenesis of type 2 diabetes. The diabetogenic effect of palmitate is achieved by increasing beta cell death through induction of the endoplasmic reticulum (ER) stress markers including activating transcription factor 3 (Atf3) and CAAT/enhancer-binding protein homologous protein-10 (Chop). In this study, we investigated whether treatment of beta cells with the MS-275, a HDAC1 and HDAC3 activity inhibitor which prevents beta cell death elicited by cytokines, is beneficial for combating beta cell dysfunction caused by palmitate. We show that culture of isolated human islets and MIN6 cells with MS-275 reduced apoptosis evoked by palmitate. The protective effect of MS-275 was associated with the attenuation of the expression of Atf3 and Chop. Silencing of HDAC3, but not of HDAC1, mimicked the effects of MS-275 on the expression of the two ER stress markers and apoptosis. These data point to HDAC3 as a potential drug target for preserving beta cells against lipotoxicity in diabetes.
authors.affiliation: European Genomic Institute for Diabetes (EGID) FR 3508, University of Lille, CNRS UMR 8199, and Faculty of Medicine West, 1 Place de Verdun, 59045 Lille, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Plaisance
authors.affiliation: European Genomic Institute for Diabetes (EGID) FR 3508, University of Lille, CNRS UMR 8199, and Faculty of Medicine West, 1 Place de Verdun, 59045 Lille, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Rolland
authors.affiliation: Department of Endocrine Surgery, Lille University Hospital, INSERM UMR 859, University of Lille, EGID FR 3508, Biotherapies for Diabetes, Lille, France.
authors.forename: Valéry
authors.initials: V
authors.lastname: Gmyr
authors.affiliation: European Genomic Institute for Diabetes (EGID) FR 3508, University of Lille, CNRS UMR 8199, and Faculty of Medicine West, 1 Place de Verdun, 59045 Lille, France.
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Annicotte
authors.affiliation: Department of Endocrine Surgery, Lille University Hospital, INSERM UMR 859, University of Lille, EGID FR 3508, Biotherapies for Diabetes, Lille, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Kerr-Conte
authors.affiliation: Department of Endocrine Surgery, Lille University Hospital, INSERM UMR 859, University of Lille, EGID FR 3508, Biotherapies for Diabetes, Lille, France.
authors.forename: François
authors.initials: F
authors.lastname: Pattou
authors.affiliation: European Genomic Institute for Diabetes (EGID) FR 3508, University of Lille, CNRS UMR 8199, and Faculty of Medicine West, 1 Place de Verdun, 59045 Lille, France.
authors.forename: Amar
authors.initials: A
authors.lastname: Abderrahmani
mesh_terms: D051700:Activating Transcription Factor 3 / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019610:Cytoprotection; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D019308:Palmitic Acid / Q000633:toxicity*; D011725:Pyridines / Q000494:pharmacology*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D046509:Tissue Culture Techniques; D051742:Transcription Factor CHOP / Q000378:metabolism; D014162:Transfection; D000099186:Histone Deacetylase 3
chemical_list: D051700:Activating Transcription Factor 3; D001549:Benzamides; D056284:Histone Deacetylase 1; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D019308:Palmitic Acid; D011725:Pyridines; D051742:Transcription Factor CHOP; D000099186:Histone Deacetylase 3; C490449:ATF3 protein, human; C103002:Atf3 protein, mouse; C497249:DDIT3 protein, human; C497250:Ddit3 protein, mouse; C118739:entinostat; C110550:HDAC1 protein, human; C484389:Hdac1 protein, mouse