Carbohydrate-Responsive Element-Binding Protein (ChREBP) Is a Negative Regulator of ARNT/HIF-1β Gene Expression in Pancreatic Islet β-Cells

Abstract

OBJECTIVECarbohydrate-responsive element-binding protein (ChREBP) is a transcription factor that has been shown to regulate carbohydrate metabolism in the liver and pancreatic β-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 β-cells.RESEARCH DESIGN AND METHODSChromatin immunoprecipitation and high-density oligonucleotide tiling arrays (ChIP-chip; Agilent Technologies) using MIN6 pancreatic β-cell extracts were performed together with transcriptional and other analysis using standard techniques.RESULTSOne 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-1β (HIF-1β), 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-1β 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-1β promoter on the proximal region that also confers the negative glucose responsiveness.CONCLUSIONSThese results demonstrate that ChREBP acts as a novel repressor of the ARNT/HIF-1β gene and might contribute to β-cell dysfunction induced by glucotoxicity.

A genome scan for selection signatures comparing farmed Atlantic salmon with two wild populations: Testing colocalization among outlier markers, candidate genes, and quantitative trait loci for production traits

“…Alleles that reduce levels of somatostatin might therefore be indirectly selected for under strong artificial selection for increased growth rates. ESTNV_35352_77 is adjacent to a carbohydrate response element transcription factor that regulates carbohydrate metabolism in the liver and pancreatic β‐cells of humans in response to high levels of glucose (Noordeen et al., 2010). Selection for high growth rates on a high carbohydrate feed diet could result in genetic changes to that have affected the expression levels of this transcription factor.…”

ChREBP Mediates Glucose Repression of Peroxisome Proliferator-activated Receptor α Expression in Pancreatic β-Cells

“…So far ChREBP has mainly been found to act as a glucose-stimulated transcriptional activator of glycolytic and lipogenic genes in hepatocytes (17)(18)(19)(20)(21) and in pancreatic ␤-cells (22,23). Recently, however, it was reported that ChREBP acts as a negative regulator of the ARNT/HIF-1␣ gene (56). We employed a combination of gain-of-function and loss-of-function experiments to investigate the possible role of ChREBP in glucose repression of PPAR␣ expression in ␤-cells.…”

Roles of Ca2+ ions in the control of ChREBP nuclear translocation

“…In addition to its lipogenic role in the liver, ChREBP is a critical regulator of lipogenic genes in the pancreatic b-cell and may play a role in the development of glucolipotoxicity and b-cell failure through lipid accumulation and apoptosis in pancreatic islets of Langerhans in response to high glucose (Wang & Wollheim 2002, da Silva Xavier et al 2006, Cha-Molstad et al 2009, Noordeen et al 2010, Boergesen et al 2011. Table 1 shows a list of significant ChREBP target genes.…”

“…It later emerged as the elusive transcription factor responsible for transmitting signal(s) generated in response to extracellular glucose to the L-type pyruvate kinase (L-PK (PKLR)) promoter in hepatocytes (Yamashita et al 2001) and orchestrating the whole lipogenic programme in concert with sterol regulatory element binding protein 1c (SREBP1c) and liver X receptor-a (LXRa NR1H3) (Foretz et al 1999, Cha & Repa 2007, Jeong et al 2011. ChREBP binds DNA as a single heterodimer with Max-like protein X (MLX) on canonical CANNTG E-box sequences, frequently not only as a repressor of transcription (Cairo et al 2001, Noordeen et al 2010) but also as an activator when two ChREBP/MLX heterodimers interact with each other on the carbohydrate response element (ChoRE, a two E-box motif separated by 5 bp) of glucose-responsive genes (Bergot et al 1992, Shih & Towle 1994, Shih et al 1995, Yamashita et al 2001, Stoeckman et al 2004, Ma et al 2007). The molecular basis of this switch is unresolved but may involve the recruitment of different sets of co-repressors or co-activators (Bricambert et al 2010, Peterson et al 2010.…”