ICER-1gamma overexpression drives palmitate-mediated connexin36 down-regulation in insulin-secreting cells.
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.
Allagnat
Florent
F
Department of Medicine, University Hospital, CHUV-1011 Lausanne, Switzerland.
Alonso
Florian
F
Martin
David
D
Abderrahmani
Amar
A
Waeber
Gérard
G
Haefliger
Jacques-Antoine
JA
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
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