Carbohydrate-responsive element-binding protein (ChREBP) is a negative regulator of ARNT/HIF-1beta gene expression in pancreatic islet beta-cells.
Diabetes
; 59(1): 153-60, 2010 Jan.
Article
em En
| MEDLINE
| ID: mdl-19833882
ABSTRACT
OBJECTIVE:
Carbohydrate-responsive element-binding protein (ChREBP) is a transcription factor that has been shown to regulate carbohydrate metabolism in the liver and pancreatic beta-cells in response to elevated glucose concentrations. Because few genes have been identified so far as bona fide ChREBP-target genes, we have performed a genome-wide analysis of the ChREBP transcriptome in pancreatic beta-cells. RESEARCH DESIGN ANDMETHODS:
Chromatin immunoprecipitation and high-density oligonucleotide tiling arrays (ChIP-chip; Agilent Technologies) using MIN6 pancreatic beta-cell extracts were performed together with transcriptional and other analysis using standard techniques.RESULTS:
One of the genes identified by ChIP-chip and linked to glucose sensing and insulin secretion was aryl hydrocarbon receptor nuclear translocator (ARNT)/hypoxia-inducible factor-1beta (HIF-1beta), a transcription factor implicated in altered gene expression and pancreatic-islet dysfunction in type 2 diabetes. We first confirmed that elevated glucose concentrations decreased ARNT/HIF-1beta levels in INS-1 (832/13) cells and primary mouse islets. Demonstrating a role for ChREBP in ARNT gene regulation, ChREBP silencing increased ARNT mRNA levels in INS-1 (832/13) cells, and ChREBP overexpression decreased ARNT mRNA in INS-1 (832/13) cells and primary mouse islets. We demonstrated that ChREBP and Max-like protein X (MLX) bind on the ARNT/HIF-1beta promoter on the proximal region that also confers the negative glucose responsiveness.CONCLUSIONS:
These results demonstrate that ChREBP acts as a novel repressor of the ARNT/HIF-1beta gene and might contribute to beta-cell dysfunction induced by glucotoxicity.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fatores de Transcrição
/
Proteínas Nucleares
/
Regulação da Expressão Gênica
/
Células Secretoras de Insulina
/
Translocador Nuclear Receptor Aril Hidrocarboneto
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Diabetes
Ano de publicação:
2010
Tipo de documento:
Article
País de afiliação:
Reino Unido