Forkhead box O1 mediates defects in palmitate-induced insulin granule exocytosis by downregulation of calcium/calmodulin-dependent serine protein kinase expression in INS-1 cells
Abstract
The transcription factor forkhead box O1 (FOXO1) induces pancreatic islet beta cell endoplasmic reticulum stress and is involved in fatty-acid-induced insulin-secretion defects. Cask is a downstream target gene of FOXO1. Using INS-1 cells with palmitate-induced insulin-release defects, we investigated the relationship between FOXO1 and Cask. The expression levels and location of calcium/calmodulin-dependent serine protein kinase (CASK) and FOXO1 were evaluated by real-time PCR, western blotting and immunofluorescence. The regulation of Cask by FOXO1 was examined using chromatin immunoprecipitation (ChIP) and luciferase assays. Potassium-stimulated insulin-secretion assays were used to verify the function of INS-1 cells and islets. Electron microscopy was used to establish the anchoring process of the insulin granules after CASK knockdown in islets. Palmitic acid reduced CASK levels and increased FOXO1 levels. ChIP and luciferase assays demonstrated FOXO1 binding with the Cask promoter, which was enhanced by palmitate treatment. CASK knockdown reduced insulin release in INS-1 cells and primary islets, and Cask overexpression reversed the palmitate-induced insulin reduction. CASK knockdown attenuated forskolin-enhanced insulin re...Continue Reading
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