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J. Biol. Chem., Vol. 283, Issue 9, 5226-5234, February 29, 2008

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 283/9/5226    most recent M708181200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Allagnat, F. Articles by Haefliger, J.-A. Search for Related Content PubMed PubMed Citation Articles by Allagnat, F. Articles by Haefliger, J.-A. Social Bookmarking                      What's this?

ICER-1 Overexpression Drives Palmitate-mediated Connexin36 Down-regulation in Insulin-secreting Cells^*

Florent Allagnat, Florian Alonso, David Martin, Amar Abderrahmani, Gérard Waeber, and Jacques-Antoine Haefliger¹

From the Department of Medicine, University Hospital, CHUV-1011 Lausanne and the Department of Cellular Biology and Morphology, University of Lausanne, 1011 Lausanne, Switzerland

Channels formed by the gap junction protein connexin36 (Cx36) contribute to the proper control of insulin secretion. We investigated the impact of chronic hyperlipidemia on Cx36 expression in pancreatic β-cells. Prolonged exposure to the saturated free fatty acid palmitate reduced the expression of Cx36 in several insulin-secreting cell lines and isolated mouse islets. The effect of palmitate was fully blocked upon protein kinase A (PKA) inhibition by H89 and (Rp)-cAMP, indicating that the cAMP/PKA pathway is involved in the control of Cx36 expression. Palmitate treatment led to overexpression of the inducible cAMP early repressor (ICER-1), which bound to a functional cAMP-response element located in the promoter of the CX36 gene. Inhibition of ICER-1 overexpression prevented the Cx36 decrease, as well as the palmitate-induced β-cell secretory dysfunction. Finally, freshly isolated islets from mice undergoing a long term high fat diet expressed reduced Cx36 levels and increased ICER-1 levels. Taken together, these data demonstrate that chronic exposure to palmitate inhibits the Cx36 expression through PKA-mediated ICER-1 overexpression. This Cx36 down-regulation may contribute to the reduced glucose sensitivity and altered insulin secretion observed during the pre-diabetic stage and in the metabolic syndrome.

Received for publication, October 2, 2007 , and in revised form, November 13, 2007.

^* This work was supported by Swiss National Science Foundation Grant 310000-109530 and grants from the Placide Nicod Foundation, the Octav and the Marcella Botnar Foundation, the Endocrinology Geneva Foundation, the Novartis Foundation, and the Emma Muschamp Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ To whom correspondence should be addressed: Dept. of Medicine, Laboratory of Molecular Medicine 19-135S, University Hospital CHUV-1011 Lausanne, Switzerland. Tel.: 41-21-314-09-26; Fax: 41-21-314-09-68; E-mail: Jacques-Antoine.Haefliger{at}chuv.ch.

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