Dataset Information

Induction of the ChREBP? Isoform Is Essential for Glucose-Stimulated ?-Cell Proliferation.

ABSTRACT: Carbohydrate-responsive element-binding protein (ChREBP) is a glucose-sensing transcription factor required for glucose-stimulated proliferation of pancreatic ?-cells in rodents and humans. The full-length isoform (ChREBP?) has a low glucose inhibitory domain (LID) that restrains the transactivation domain when glucose catabolism is minimal. A novel isoform of ChREBP (ChREBP?) was recently described that lacks the LID domain and is therefore constitutively and more potently active. ChREBP? has not been described in ?-cells nor has its role in glucose-stimulated proliferation been determined. We found that ChREBP? is highly expressed in response to glucose, particularly with prolonged culture in hyperglycemic conditions. In addition, small interfering RNAs that knocked down ChREBP? transcripts without affecting ChREBP? expression or activity decreased glucose-stimulated expression of carbohydrate response element-containing genes and glucose-stimulated proliferation in INS-1 cells and in isolated rat islets. Quantitative chromatin immunoprecipitation, electrophoretic mobility shift assays, and luciferase reporter assays were used to demonstrate that ChREBP binds to a newly identified powerful carbohydrate response element in ?-cells and hepatocytes, distinct from that in differentiated 3T3-L1 adipocytes. We conclude that ChREBP? contributes to glucose-stimulated gene expression and proliferation in ?-cells, with recruitment of ChREBP? to tissue-specific elements of the ChREBP? isoform promoter.

SUBMITTER: Zhang P

PROVIDER: S-EPMC4657577 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Induction of the ChREBPβ Isoform Is Essential for Glucose-Stimulated β-Cell Proliferation.

Zhang Pili P Kumar Anil A Katz Liora S LS Li Lucy L Paulynice Martine M Herman Mark A MA Scott Donald K DK

Diabetes 20150917 12

Carbohydrate-responsive element-binding protein (ChREBP) is a glucose-sensing transcription factor required for glucose-stimulated proliferation of pancreatic β-cells in rodents and humans. The full-length isoform (ChREBPα) has a low glucose inhibitory domain (LID) that restrains the transactivation domain when glucose catabolism is minimal. A novel isoform of ChREBP (ChREBPβ) was recently described that lacks the LID domain and is therefore constitutively and more potently active. ChREBPβ has n ...[more]

PMID: 26384380

Similar Datasets

Project description:Carbohydrate response element binding protein (ChREBP) is a lipogenic transcription factor that is thought to be involved in the development of hepatic steatosis and insulin resistance. Increased ChREBP expression in liver results in increased hepatic steatosis, and the isoform ChREBP? in adipose tissue can predict insulin sensitivity in obese humans. As ChREBP is activated by glucose, it was postulated that the composition of diet would regulate ChREBP isoform expression in metabolically relevant tissues. We compared the effects of diets with high complex carbohydrate, high fat, or a normal chow on ChREBP expression and metabolic parameters in C57BL/6 mice. We found that diets high in fat decrease ChREBP expression in adipose tissue, but isocaloric diets high in carbohydrate have no effect. Interestingly, this decrease in adipose ChREBP was associated with increased inflammatory markers. In the same animals a high carbohydrate diet induced a robust increase in hepatic ChREBP? expression (?2-fold; p = 0.0002), but little detectable change in the more abundant ChREBP? transcript. This change was accompanied by increased expression of target genes liver pyruvate kinase (p<0.0001), acetyl-CoA carboxylase (p = 0.0191) and stearoyl-CoA desaturase-1 (p = 0.0045). This increase in ChREBP expression was associated with increased hepatic steatosis, despite no changes in body weight or body fat when compared to chow-fed mice. Unexpectedly, mice fed a high carbohydrate diet displayed enhanced sensitivity to exogenous insulin, despite having mild glucose intolerance and increased liver steatosis. In summary, we have shown the composition of diet can selectively regulate ChREBP isoform expression in a tissue specific manner. Furthermore, we have shown a high complex carbohydrate diet selectively increases hepatic ChREBP? expression, which associates with hepatic steatosis but not insulin resistance. In contrast, a high fat diet reduces adipose ChREBP, which associates with inflammation and insulin resistance.

Dataset Information

Induction of the ChREBP? Isoform Is Essential for Glucose-Stimulated ?-Cell Proliferation.

Publications

Induction of the ChREBPβ Isoform Is Essential for Glucose-Stimulated β-Cell Proliferation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure