title: Reduction of connexin36 content by ICER-1 contributes to insulin-secreting cells apoptosis induced by oxidized LDL particles.
abstract: Connexin36 (Cx36), a trans-membrane protein that forms gap junctions between insulin-secreting beta-cells in the Langerhans islets, contributes to the proper control of insulin secretion and beta-cell survival. Hypercholesterolemia and pro-atherogenic low density lipoproteins (LDL) contribute to beta-cell dysfunction and apoptosis in the context of Type 2 diabetes. We investigated the impact of LDL-cholesterol on Cx36 levels in beta-cells. As compared to WT mice, the Cx36 content was reduced in islets from hypercholesterolemic ApoE-/- mice. Prolonged exposure to human native (nLDL) or oxidized LDL (oxLDL) particles decreased the expression of Cx36 in insulin secreting cell-lines and isolated rodent islets. Cx36 down-regulation was associated with overexpression of the inducible cAMP early repressor (ICER-1) and the selective disruption of ICER-1 prevented the effects of oxLDL on Cx36 expression. Oil red O staining and Plin1 expression levels suggested that oxLDL were less stored as neutral lipid droplets than nLDL in INS-1E cells. The lipid beta-oxidation inhibitor etomoxir enhanced oxLDL-induced apoptosis whereas the ceramide synthesis inhibitor myriocin partially protected INS-1E cells, suggesting that oxLDL toxicity was due to impaired metabolism of the lipids. ICER-1 and Cx36 expressions were closely correlated with oxLDL toxicity. Cx36 knock-down in INS-1E cells or knock-out in primary islets sensitized beta-cells to oxLDL-induced apoptosis. In contrast, overexpression of Cx36 partially protected INS-1E cells against apoptosis. These data demonstrate that the reduction of Cx36 content in beta-cells by oxLDL particles is mediated by ICER-1 and contributes to oxLDL-induced beta-cell apoptosis.
authors: Service of Internal Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors: Jacques-Antoine
authors: JA
authors: Haefliger
authors: David
authors: D
authors: Martin
authors: Dimitri
authors: D
authors: Favre
authors: Yannick
authors: Y
authors: Petremand
authors: Lucia
authors: L
authors: Mazzolai
authors: Amar
authors: A
authors: Abderrahmani
authors: Paolo
authors: P
authors: Meda
authors: Gérard
authors: G
authors: Waeber
authors: Florent
authors: F
authors: Allagnat
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects*; D001391:Azo Compounds; D015153:Blotting, Western; D002352:Carrier Proteins; D002460:Cell Line; D017630:Connexins / Q000378:metabolism*; D051786:Cyclic AMP Response Element Modulator / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D006937:Hypercholesterolemia / Q000503:physiopathology*; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000502:physiology*; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008156:Luciferases; D051379:Mice; D018345:Mice, Knockout; D000070778:Perilipin-1; D010750:Phosphoproteins; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D000097004:Gap Junction delta-2 Protein
chemical_list: D001057:Apolipoproteins E; D001391:Azo Compounds; D002352:Carrier Proteins; D017630:Connexins; D051786:Cyclic AMP Response Element Modulator; D017931:DNA Primers; D008077:Lipoproteins, LDL; D008156:Luciferases; D000070778:Perilipin-1; D010750:Phosphoproteins; D000097004:Gap Junction delta-2 Protein; C497411:Crem protein, mouse; C000602978:PLIN1 protein, human; C000602979:Plin1 protein, mouse; C000602981:Plin1 protein, rat; C099252:oxidized low density lipoprotein; C011049:oil red O
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