详细记录  
题名:Reduction of connexin36 content by ICER-1 contributes to insulin-secreting cells apoptosis induced by oxidized LDL particles.
作者:HAEFLIGER JA; MARTIN D; FAVRE D; PETREMAND Y; MAZZOLAI L; ABDERRAHMANI A; MEDA P; WAEBER G; ALLAGNAT F;
来源:PLoS One. 2013;8(1):e55198. doi: 10.1371/journal.pone.0055198. Epub 2013 Jan 30. [ IF= 4.09 ] ]
URL :10.1371/journal.pone.0055198
日期:20130131
摘要: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.

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