ChREBP Rather than USF2 Regulates Glucose Stimulation of Endogenous L-pyruvate Kinase Expression in Insulin-secreting Cells

Wang, Haiyan; Wollheim, Claes B.

doi:10.1074/jbc.m201635200

Cited by 89 publications

(86 citation statements)

References 18 publications

(57 reference statements)

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“…1D), and although USF2 may be involved in general modulation of txnip transcription (data not shown), ChIP analysis failed to reveal any increase in USF2 recruitment to the txnip promoter in response to glucose, suggesting that USF2 is not mediating the glucose effects. This is consistent with previous finding in regard to the regulation of LPK in beta cells (20). In contrast, Mlx, the heterodimeric ChREBP partner, also bound to the txnip promoter, and its binding activity was increased in response to high glucose (Fig.…”

Section: Discussionsupporting

confidence: 82%

“…Very similar effects were also observed with another primer pair (data not shown). ChREBP is known to mediate glucose-induced transactivation of liver-type pyruvate kinase (LPK) in the liver as well as in beta cells (18,20) and was therefore used as a positive control. Indeed, glucose led to a similar induction of ChREBP binding to the LPK promoter, although the level of ChREBP binding to the txnip promoter was higher overall (Fig.…”

Section: The Txnip Promoter Contains a Putative Chrebp Binding Site-mentioning

confidence: 99%

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Glucose-stimulated Expression of Txnip Is Mediated by Carbohydrate Response Element-binding Protein, p300, and Histone H4 Acetylation in Pancreatic Beta Cells

Cha-Molstad

Saxena

Chen

et al. 2009

Journal of Biological Chemistry

199

219

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Recently, we identified Txnip (thioredoxin-interacting protein) as a mediator of glucotoxic beta cell death and discovered that lack of Txnip protects against streptozotocin-and obesityinduced diabetes by preventing beta cell apoptosis and preserving endogenous beta cell mass. Txnip has therefore become an attractive target for diabetes therapy, but although we have found that txnip transcription is highly induced by glucose through a unique carbohydrate response element, the factors controlling this effect have remained unknown. Using transient transfection experiments, we now show that overexpression of the carbohydrate response element-binding protein (ChREBP) transactivates the txnip promoter, whereas ChREBP knockdown by small interfering RNA completely blunts glucose-induced txnip transcription. Moreover, chromatin immunoprecipitation demonstrated that glucose leads to a dose-and time-dependent recruitment of ChREBP to the txnip promoter in vivo in INS-1 beta cells as well as human islets. Furthermore, we found that the co-activator and histone acetyltransferase p300 co-immunoprecipitates with ChREBP and also binds to the txnip promoter in response to glucose. Interestingly, this is associated with specific acetylation of histone H4 and recruitment of RNA polymerase II as measured by chromatin immunoprecipitation. Thus, with this study we have identified ChREBP as the transcription factor that mediates glucose-induced txnip expression in human islets and INS-1 beta cells and have characterized the chromatin modification associated with glucose-induced txnip transcription. In addition, the results reveal for the first time that ChREBP interacts with p300. This may explain how ChREBP induces H4 acetylation and sheds new light on glucose-mediated regulation of chromatin structure and transcription.

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Section: Discussionsupporting

confidence: 82%

Section: The Txnip Promoter Contains a Putative Chrebp Binding Site-mentioning

confidence: 99%

Glucose-stimulated Expression of Txnip Is Mediated by Carbohydrate Response Element-binding Protein, p300, and Histone H4 Acetylation in Pancreatic Beta Cells

Cha-Molstad

Saxena

Chen

et al. 2009

Journal of Biological Chemistry

199

219

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“…In hepatocytes, high glucose concentrations activate the transcription factor known as carbohydrate response elementbinding protein (ChREBP), a key inducer of glycolysis and lipogenesis [4]. ChREBP is also expressed in beta cells where it regulates expression of glycolytic and lipogenic genes and contributes to glucose-stimulated beta cell proliferation [5][6][7]. A major function of pancreatic beta cells is to secrete insulin in response to a rise in circulating glucose concentrations, and the signalling pathway involved depends on glucose metabolism [8].…”

Section: Introductionmentioning

confidence: 99%

GLUT2, glucose sensing and glucose homeostasis

2014

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The glucose transporter isoform GLUT2 is expressed in liver, intestine, kidney and pancreatic islet beta cells, as well as in the central nervous system, in neurons, astrocytes and tanycytes. Physiological studies of genetically modified mice have revealed a role for GLUT2 in several regulatory mechanisms. In pancreatic beta cells, GLUT2 is required for glucose-stimulated insulin secretion. In hepatocytes, suppression of GLUT2 expression revealed the existence of an unsuspected glucose output pathway that may depend on a membrane traffic-dependent mechanism. GLUT2 expression is nevertheless required for the physiological control of glucose-sensitive genes, and its inactivation in the liver leads to impaired glucose-stimulated insulin secretion, revealing a liver-beta cell axis, which is likely to be dependent on bile acids controlling beta cell secretion capacity. In the nervous system, GLUT2-dependent glucose sensing controls feeding, thermoregulation and pancreatic islet cell mass and function, as well as sympathetic and parasympathetic activities. Electrophysiological and optogenetic techniques established that Glut2 (also known as Slc2a2)-expressing neurons of the nucleus tractus solitarius can be activated by hypoglycaemia to stimulate glucagon secretion. In humans, inactivating mutations in GLUT2 cause Fanconi-Bickel syndrome, which is characterised by hepatomegaly and kidney disease; defects in insulin secretion are rare in adult patients, but GLUT2 mutations cause transient neonatal diabetes. Genome-wide association studies have reported that GLUT2 variants increase the risks of fasting hyperglycaemia, transition to type 2 diabetes, hypercholesterolaemia and cardiovascular diseases. Individuals with a missense mutation in GLUT2 show preference for sugar-containing foods. We will discuss how studies in mice help interpret the role of GLUT2 in human physiology.

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“…It was reported that L-PK promoter activity can be upregulated by ChREBP in high-glucose medium in INS-1, an insulinoma cell line (24,25). In this study, we used a particularly glucose-sensitive cell line, INS-1-derived 832/13 (22).…”

mentioning

confidence: 99%

Glucose-Dependent Transcriptional Regulation by an Evolutionarily Conserved Glucose-Sensing Module

et al. 2006

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We report here a novel mechanism for glucose-mediated activation of carbohydrate response element binding protein (ChREBP), a basic helix-loop-helix/leucine zipper (bHLH/ZIP) transcription factor of Mondo family that binds to carbohydrate response element in the promoter of some glucose-regulated genes and activates their expression upon glucose stimulation. Structure-function analysis of ChREBP in a highly glucose-sensitive system using GAL4-ChREBP fusion constructs revealed a glucose-sensing module (GSM) that mediates glucose responsiveness of ChREBP. GSM is conserved among Mondo family members; MondoA, a mammalian paralog of unknown function, and the GSM region of a Drosophila homolog were also found to be glucose responsive. GSM is composed of a low-glucose inhibitory domain (LID) and a glucose-response activation conserved element (GRACE). We have identified a new mechanism accounting for glucose responsiveness of ChREBP that involves specific inhibition of the transactivation activity of GRACE by LID under low glucose concentration and reversal of this inhibition by glucose in an orientation-sensitive manner. The intramolecular inhibition and its release by glucose is a regulatory mechanism that is independent of changes of subcellular localization or DNA binding activity, events that also appear to be involved in glucose responsiveness. This evolutionally conserved mechanism may play an essential role in glucose-responsive gene regulation.

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ChREBP Rather than USF2 Regulates Glucose Stimulation of Endogenous L-pyruvate Kinase Expression in Insulin-secreting Cells

Cited by 89 publications

References 18 publications

Glucose-stimulated Expression of Txnip Is Mediated by Carbohydrate Response Element-binding Protein, p300, and Histone H4 Acetylation in Pancreatic Beta Cells

Glucose-stimulated Expression of Txnip Is Mediated by Carbohydrate Response Element-binding Protein, p300, and Histone H4 Acetylation in Pancreatic Beta Cells

GLUT2, glucose sensing and glucose homeostasis

Glucose-Dependent Transcriptional Regulation by an Evolutionarily Conserved Glucose-Sensing Module

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