Abstract:
:Tight regulation of fatty acid metabolism in pancreatic beta-cells is important for beta-cell viability and function. Chronic exposure to elevated concentrations of fatty acid is associated with beta-cell lipotoxicity. Glucose is known to repress fatty acid oxidation and hence to augment the toxicity of fatty acids. The peroxisome proliferator activated receptor alpha (PPARalpha) is a key activator of genes involved in beta-cell fatty acid oxidation, and transcription of the PPARalpha gene has been shown to be repressed by increasing concentrations of glucose in beta-cells. However, the mechanism underlying this transcriptional repression by glucose remains unclear. Here we report that glucose-induced repression of PPARalpha gene expression in INS-1E cells is independent of beta-cell excitation and insulin secretion but requires activation of protein phosphatase 2A in a process involving inactivation of the AMP-activated protein kinase (AMPK). Pharmacological activation of AMPK at high glucose concentrations interferes with glucose repression of PPARalpha and PPARalpha target genes in INS-1E cells as well as in rat islets. Specific knock-down of the catalytic AMPK-subunit AMPKalpha2 but not AMPKalpha1 using RNAi suppressed PPARalpha expression, thereby mimicking the effect of glucose. These results indicate that activation of protein phosphatase 2A and subsequent inactivation of AMPK is necessary for glucose repression of PPARalpha expression in pancreatic beta-cells.
journal_name
J Mol Endocrinoljournal_title
Journal of molecular endocrinologyauthors
Ravnskjaer K,Boergesen M,Dalgaard LT,Mandrup Sdoi
10.1677/jme.1.01965subject
Has Abstractpub_date
2006-04-01 00:00:00pages
289-99issue
2eissn
0952-5041issn
1479-6813pii
36/2/289journal_volume
36pub_type
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