Dataset Information
Islet ChREBP-? is increased in diabetes and controls ChREBP-? and glucose-induced gene expression via a negative feedback loop.
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ABSTRACT: Objective
Carbohydrate-response element-binding protein (ChREBP) is the major transcription factor conferring glucose-induced gene expression in pancreatic islets, liver and adipose tissue. Recently, a novel ChREBP isoform, ChREBP-?, was identified in adipose tissue and found to be also expressed in islets and involved in glucose-induced beta cell proliferation. However, the physiological function of this less abundant ?-isoform in the islet, and in diabetes, is largely unknown. The aims of the present study, therefore, were to determine how diabetes affects ChREBP-? and elucidate its physiological role in pancreatic beta cells.Methods
Non-obese diabetic and obese, diabetic ob/ob mice were used as models of T1D and T2D and human islets and the rat INS-1 beta cell line were exposed to low/high glucose and used for ChREBP isoform-specific gain-and-loss-of-function experiments. Changes in ChREBP-? and ChREBP-? were assessed by qRT-PCR, immunoblotting, promoter luciferase, and chromatin immunoprecipitation studies.Results
Expression of the ChREBP-? isoform was highly induced in diabetes and by glucose, whereas ChREBP-? was downregulated. Interestingly, ChREBP-? gain-of-function experiments further revealed that it was ChREBP-? that downregulated ChREBP-? through a negative feedback loop. On the other hand, ChREBP-? knockdown led to unabated ChREBP-? activity and glucose-induced expression of target genes, suggesting that one of the physiological roles of this novel ?-isoform is to help keep glucose-induced and ChREBP-?-mediated gene expression under control.Conclusions
We have identified a previously unappreciated negative feedback loop by which glucose-induced ChREBP-? downregulates ChREBP-?-signaling providing new insight into the physiological role of islet ChREBP-? and into the regulation of glucose-induced gene expression.
SUBMITTER: Jing G
PROVIDER: S-EPMC5123192 | biostudies-literature | 2016 Dec
REPOSITORIES: biostudies-literature
Publications
Islet ChREBP-β is increased in diabetes and controls ChREBP-α and glucose-induced gene expression via a negative feedback loop.
Molecular metabolism 20160930 12
<h4>Objective</h4>Carbohydrate-response element-binding protein (ChREBP) is the major transcription factor conferring glucose-induced gene expression in pancreatic islets, liver and adipose tissue. Recently, a novel ChREBP isoform, ChREBP-β, was identified in adipose tissue and found to be also expressed in islets and involved in glucose-induced beta cell proliferation. However, the physiological function of this less abundant β-isoform in the islet, and in diabetes, is largely unknown. The aims ...[more]