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: Jacques-Antoine Haefliger, David Martin, Dimitri Favre, Yannick Petremand, Lucia Mazzolai, Amar Abderrahmani, Paolo Meda, Gérard Waeber, Florent Allagnat
• Journal: PloS one (PLoS One) Vol. 8 Issue 1 Pg. e55198 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23383107 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apolipoproteins E
• Azo Compounds
• Carrier Proteins
• Connexins
• Crem protein, mouse
• DNA Primers
• Lipoproteins, LDL
• PLIN1 protein, human
• Perilipin-1
• Phosphoproteins
• Plin1 protein, mouse
• Plin1 protein, rat
• connexin 36
• oxidized low density lipoprotein
• Cyclic AMP Response Element Modulator
• Luciferases
• oil red O

Topics

• Analysis of Variance
• Animals
• Apolipoproteins E (genetics)
• Apoptosis (drug effects)
• Azo Compounds
• Blotting, Western
• Carrier Proteins
• Cell Line
• Connexins (metabolism)
• Cyclic AMP Response Element Modulator (metabolism)
• DNA Primers (genetics)
• Gene Expression Regulation (drug effects)
• Humans
• Hypercholesterolemia (physiopathology)
• Insulin-Secreting Cells (drug effects, physiology)
• Lipoproteins, LDL (pharmacology)
• Luciferases
• Mice
• Mice, Knockout
• Perilipin-1
• Phosphoproteins
• Rats
• Real-Time Polymerase Chain Reaction