Abstract
Carbohydrate responsive element-binding protein (ChREBP) is a transcription factor whose expression and activity are increased in pancreatic β-cells maintained at elevated glucose concentrations. We show here that ChREBP inactivation in clonal pancreatic MIN6 β-cells results in an increase in Pdx-1 expression at low glucose and to a small, but significant, increase in Ins2, GcK and MafA gene expression at high glucose concentrations. Conversely, adenovirus-mediated over-expression of ChREBP in mouse pancreatic islets results in decreases in Pdx-1, MafA, Ins1, Ins2 and GcK mRNA levels. These data suggest that strategies to reduce ChREBP activity might protect against β-cell dysfunction in type 2 diabetes.
Highlights
Pancreatic b-cell glucolipotoxicity [1] is considered to play a significant role in the pathogenesis of type 2 diabetes
Others, have previously shown that, in pancreatic b-cells, Carbohydrate responsive element-binding protein (ChREBP) is activated by high glucose and is responsible for the induction of the lipogenic genes fatty acid synthase (FAS) and Abbreviations: ARNT, aryl hydrocarbon receptor nuclear translocator; ChREBP, carbohydrate responsive element-binding protein; ChIP, chromatin immunoprecipitation; ChoRE, carbohydrate-responsive element; FAS, fatty acid synthase; GcK, glucokinase; GFP, green fluorescent protein; HIF, hypoxia inducible factor; L-type pyruvate kinase (L-PK), Ltype pyruvate kinase; pancreatic and duodenal homeobox-1 (Pdx-1), pancreatic and duodenum homeobox-1; siRNA, small interfering RNA; SREBP-1c, sterol regulatory response-element-binding protein-1c; USF, upstream stimulatory factor
ChREBP knockdown increased the levels of mRNA encoding MafA, GcK and Ins2 at high (30 mM) glucose concentrations, whereas ChREBP silencing increased the expression of the Pdx-1 gene at low (3 mM) glucose concentrations (Table 2 and Fig. 1A)
Summary
Pancreatic b-cell glucolipotoxicity [1] is considered to play a significant role in the pathogenesis of type 2 diabetes. Others, have previously shown that, in pancreatic b-cells, ChREBP is activated by high glucose and is responsible for the induction of the lipogenic genes fatty acid synthase (FAS) and Abbreviations: ARNT, aryl hydrocarbon receptor nuclear translocator; ChREBP, carbohydrate responsive element-binding protein; ChIP, chromatin immunoprecipitation; ChoRE, carbohydrate-responsive element; FAS, fatty acid synthase; GcK, glucokinase; GFP, green fluorescent protein; HIF, hypoxia inducible factor; L-PK, Ltype pyruvate kinase; Pdx-1, pancreatic and duodenum homeobox-1; siRNA, small interfering RNA; SREBP-1c, sterol regulatory response-element-binding protein-1c; USF, upstream stimulatory factor. ChREBP represses aryl hydrocarbon receptor nuclear translocator/hypoxia inducible factor 1-b (ARNT/HIF1-b) [13] shown recently to be diminished in islets [14] and liver [15] of type 2 diabetic humans, and necessary for normal b-cell function and repression of hepatic gluconeogenesis. We sought here to investigate the effects of ChREBP silencing and over-expression on other key glucose-responsive genes in pancreatic islet b-cells, namely pancreatic and duodenal homeobox-1 (Pdx-1), MafA, glucokinase (GcK) and insulin, all critical for normal pancreatic b-cell function
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