Palmitate Inhibition of Insulin Gene Expression Is Mediated at the Transcriptional Level via Ceramide Synthesis

Chronic exposure to elevated levels of fatty acids impairs pancreatic beta cell function, a phenomenon thought to contribute to the progressive deterioration of insulin secretion in type 2 diabetes. We have previously demonstrated that prolonged exposure of isolated islets to elevated levels of palm...

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Published in:The Journal of biological chemistry 2003-08, Vol.278 (32), p.30015-30021
Main Authors: Kelpe, Cynthia L., Moore, Patrick C., Parazzoli, Susan D., Wicksteed, Barton, Rhodes, Christopher J., Poitout, Vincent
Format: Article
Language:English
Subjects:
Adenoviridae - genetics
Animals
Cell Separation
Cell Survival
Cells, Cultured
Ceramides - metabolism
Chromatography, Thin Layer
Dose-Response Relationship, Drug
Flow Cytometry
Gene Expression Regulation
Glucose - metabolism
Glucose - pharmacology
Insulin - biosynthesis
Insulin - genetics
Islets of Langerhans - cytology
Luciferases - metabolism
Male
Microscopy, Confocal
Palmitic Acid - pharmacology
Rats
Rats, Wistar
Ribonucleases - metabolism
RNA, Messenger - metabolism
Time Factors
Transcription, Genetic
Transfection
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Summary:Chronic exposure to elevated levels of fatty acids impairs pancreatic beta cell function, a phenomenon thought to contribute to the progressive deterioration of insulin secretion in type 2 diabetes. We have previously demonstrated that prolonged exposure of isolated islets to elevated levels of palmitate inhibits preproinsulin mRNA levels in the presence of high glucose concentrations. However, whether this occurs via transcriptional or post-transcriptional mechanisms has not been determined. In addition, the nature of the lipid metabolites involved in palmitate inhibition of insulin gene expression is unknown. In this study, we show that palmitate decreases glucose-stimulated preproinsulin mRNA levels in isolated rat islets, an effect that is not mediated by changes in preproinsulin mRNA stability, but is associated with inhibition of glucose-stimulated insulin promoter activity. Prolonged culture of isolated islets with palmitate is associated with increased levels of intracellular ceramide. Palmitate-induced ceramide generation is prevented by inhibitors of de novo ceramide synthesis. Further, exogenous ceramide inhibits insulin mRNA levels, whereas blockade of de novo ceramide synthesis prevents palmitate inhibition of insulin gene expression. We conclude that prolonged exposure to elevated levels of palmitate affects glucose-stimulated insulin gene expression via transcriptional mechanisms and ceramide synthesis.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M302548200