ICER-1gamma overexpression drives palmitate-mediated connexin36 down-regulation in insulin-secreting cells.

Details

Serval ID
serval:BIB_DD9E73B6B269
Type
Article: article from journal or magazin.
Collection
Publications
Title
ICER-1gamma overexpression drives palmitate-mediated connexin36 down-regulation in insulin-secreting cells.
Journal
Journal of Biological Chemistry
Author(s)
Allagnat F., Alonso F., Martin D., Abderrahmani A., Waeber G., Haefliger J.A.
ISSN
0021-9258
Publication state
Published
Issued date
2008
Peer-reviewed
Oui
Volume
283
Number
9
Pages
5226-5234
Language
english
Notes
Publication types: Journal Article
Abstract
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 beta-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-1gamma), which bound to a functional cAMP-response element located in the promoter of the CX36 gene. Inhibition of ICER-1gamma overexpression prevented the Cx36 decrease, as well as the palmitate-induced beta-cell secretory dysfunction. Finally, freshly isolated islets from mice undergoing a long term high fat diet expressed reduced Cx36 levels and increased ICER-1gamma levels. Taken together, these data demonstrate that chronic exposure to palmitate inhibits the Cx36 expression through PKA-mediated ICER-1gamma 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.
Keywords
Animals, Cell Line, Tumor, Connexins/biosynthesis, Connexins/genetics, Cyclic AMP/analogs & derivatives, Cyclic AMP/pharmacology, Cyclic AMP Response Element Modulator/biosynthesis, Cyclic AMP Response Element Modulator/genetics, Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors, Cyclic AMP-Dependent Protein Kinases/genetics, Diabetes Mellitus/genetics, Diabetes Mellitus/metabolism, Diet, Atherogenic, Dietary Fats/adverse effects, Dietary Fats/pharmacology, Down-Regulation/drug effects, Gap Junctions/genetics, Gap Junctions/metabolism, Insulin/genetics, Insulin/secretion, Insulin-Secreting Cells/pathology, Insulin-Secreting Cells/secretion, Isoquinolines/pharmacology, Metabolic Syndrome X/genetics, Metabolic Syndrome X/metabolism, Mice, Palmitic Acid/pharmacology, Protein Kinase Inhibitors/pharmacology, Rats, Sulfonamides/pharmacology, Thionucleotides/pharmacology
Pubmed
Web of science
Open Access
Yes
Create date
17/11/2008 9:57
Last modification date
02/09/2019 10:58
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