Role of the transcriptional factor C/EBPbeta in free fatty acid-elicited beta-cell failure.
Fatty acids can favour the development of Type 2 diabetes by reducing insulin secretion and inducing apoptosis of pancreatic beta-cells. Here, we show that sustained exposure of the beta-cell line MIN6 or of isolated pancreatic islets to the most abundant circulating fatty acid palmitate increases the level of C/EBPbeta, an insulin transcriptional repressor. In contrast, two unsaturated fatty acids, oleate and linoleate were without effect. The induction of C/EBPbeta elicited by palmitate was prevented by inhibiting the ERK1/2 MAP kinase pathway or by reducing mitochondrial fatty acid oxidation with an inhibitor of Carnitine Palmitoyl Transferase-1. Overexpression of C/EBPbeta mimicked the detrimental effects of palmitate and resulted in a drastic reduction in insulin promoter activity, impairment in the capacity to respond to secretory stimuli and an increase in apoptosis. Our data suggest a potential involvement of C/EBPbeta as mediator of the deleterious effects of unsaturated free fatty acids on beta-cell function.
Plaisance
Valérie
V
Department of Cell Biology and Morphology, Faculty of Biology and Medicine, University of Lausanne, Rue du Bugnon 9, 1005 Lausanne, Switzerland.
Perret
Véronique
V
Favre
Dimitri
D
Abderrahmani
Amar
A
Yang
Jiang-Yan
JY
Widmann
Christian
C
Regazzi
Romano
R
D017209:Apoptosis / Q000187:drug effects*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002334:Carnitine O-Palmitoyltransferase / Q000494:pharmacology; D002460:Cell Line; D007328:Insulin / Q000096:biosynthesis; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects*; D019787:Linoleic Acid / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D019301:Oleic Acid / Q000494:pharmacology; D010084:Oxidation-Reduction; D010168:Palmitates / Q000494:pharmacology*
D022782:CCAAT-Enhancer-Binding Protein-beta; D007328:Insulin; D010168:Palmitates; D019301:Oleic Acid; D019787:Linoleic Acid; D002334:Carnitine O-Palmitoyltransferase