title: ICER-1gamma overexpression drives palmitate-mediated connexin36 down-regulation in insulin-secreting cells.
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.
authors: Department of Medicine, University Hospital, CHUV-1011 Lausanne, Switzerland.
authors: Florent
authors: F
authors: Allagnat
authors: Florian
authors: F
authors: Alonso
authors: David
authors: D
authors: Martin
authors: Amar
authors: A
authors: Abderrahmani
authors: Gérard
authors: G
authors: Waeber
authors: Jacques-Antoine
authors: JA
authors: Haefliger
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D017630:Connexins / Q000096:biosynthesis* / Q000235:genetics; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D051786:Cyclic AMP Response Element Modulator / Q000096:biosynthesis* / Q000235:genetics; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism; D004036:Diet, Atherogenic; D004041:Dietary Fats / Q000009:adverse effects / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects*; D017629:Gap Junctions / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D007546:Isoquinolines / Q000494:pharmacology; D024821:Metabolic Syndrome / Q000235:genetics / Q000378:metabolism; D051379:Mice; D019308:Palmitic Acid / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D013449:Sulfonamides / Q000494:pharmacology; D013873:Thionucleotides / Q000494:pharmacology; D000097004:Gap Junction delta-2 Protein
chemical_list: D017630:Connexins; D000242:Cyclic AMP; D051786:Cyclic AMP Response Element Modulator; D017868:Cyclic AMP-Dependent Protein Kinases; D004041:Dietary Fats; D007328:Insulin; D007546:Isoquinolines; D019308:Palmitic Acid; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D013873:Thionucleotides; D000097004:Gap Junction delta-2 Protein; C016957:adenosine-3',5'-cyclic phosphorothioate; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide