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

Diabetologia
Yao WangXiao Han

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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Citations

Jan 3, 2018·Acta Biochimica Et Biophysica Sinica·Yao WangYuexing Yuan
Jun 7, 2019·Acta Biochimica Et Biophysica Sinica·Kai ZhangYao Wang
Jul 26, 2019·Cell Biology International·Linglin QianLiqun Ren
Jul 4, 2020·Genes & Development·Biliana MarchevaJoseph Bass
Mar 19, 2020·International Journal of Endocrinology·Wei XuJun Liang
Nov 8, 2020·Molecular and Cellular Endocrinology·Kai ZhangYao Wang
Nov 15, 2020·Journal of Cellular and Molecular Medicine·Tian-Yuan WangYao Wang
Mar 9, 2021·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·Matteo Antoine NegroniSusanne Foitzik

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