Regulation of the uncoupling protein-2 gene in INS-1 beta-cells by oleic acid.

Medvedev AV, Robidoux J, Bai X, Cao W, Floering LM, Daniel KW, Collins S
J Biol Chem. 2002 277 (45): 42639-44

PMID: 12205102 · DOI:10.1074/jbc.M208645200

Current evidence suggests that uncoupling protein-2 (UCP2) is a regulator of insulin secretion. It is also known that chronic exposure of pancreatic islets to free fatty acids (FFAs) blunts glucose-stimulated insulin secretion and is accompanied by elevated levels of UCP2. However, the mechanisms regulating expression of UCP2 in beta-cells are unknown. Here, we show that UCP2 mRNA and protein levels were increased after a 48-h exposure of INS-1(832/13) beta-cells to oleic acid (0.5 mm) by activation of the UCP2 promoter. Furthermore, progressive deletions of the mouse UCP2 promoter (from -7.3 kb to +12 bp) indicated that an enhancer region (-86/-44) was responsible for both basal and FFA-stimulated UCP2 gene transcription. This enhancer contains tightly clustered Sp1, sterol regulatory element (SRE), and double E-Box elements. While all three sequence motifs were required for basal activity of the UCP2 promoter, the mutations in either the SRE or the E-Box elements eliminated the response to FFAs. The SRE and sterol regulatory element binding protein-1 (SREBP1) appear to be crucial for the response of the UCP2 gene to FFAs, since overexpression of the nuclear forms of the SREBPs increased UCP2 promoter activity by 7-10-fold and restored the ability of E-Box mutants to respond to oleic acid. These data support a model in which SREBP is the major modulator of UCP2 gene transcription by FFA, while E-Box binding factors play a supportive role.

MeSH Terms (23)

Animals Base Sequence CCAAT-Enhancer-Binding Proteins Cell Line DNA-Binding Proteins Enhancer Elements, Genetic Gene Expression Regulation Ion Channels Islets of Langerhans Membrane Transport Proteins Mitochondrial Proteins Mutagenesis Mutagenesis, Site-Directed Oleic Acid Point Mutation Proteins Recombinant Proteins Sequence Deletion Sterol Regulatory Element Binding Protein 1 Transcription Factors Transfection Uncoupling Agents Uncoupling Protein 2

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