Up-regulation of O-GlcNAc Transferase with Glucose Deprivation in HepG2 Cells Is Mediated by Decreased Hexosamine Pathway Flux

Taylor, Rodrick P.; Geisler, Taylor S.; Chambers, Jefferson; McClain, Donald A.

doi:10.1074/jbc.m803198200

Cited by 93 publications

(102 citation statements)

References 29 publications

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“…OGT and OGA mRNA expression increased, whereas OGA protein levels decreased and there was no change in OGT protein expression. Similar studies showed an increase in O-GlcNAc levels with glucose deprivation, while the changes in expression and activity of O-GlcNAc enzymes varied between different cell lines, suggesting the response is celltype dependent [36,37]. A rapid augmentation of O-GlcNAcylation with heat stress was reported, but there were no significant changes in the mRNA expression and activity of OGT, OGA, and the levels of UDP-GlcNAc [38].…”

Section: Mrna Expression Of the O-glcnac Cycling Enzymesmentioning

confidence: 66%

Glutathione depletion and acute exercise increase O-GlcNAc protein modification in rat skeletal muscle

et al. 2014

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Post-translational modification of intracellular proteins with O-linked β-N-acetylglucosamine (O-GlcNAc) profoundly affects protein structure, function, and metabolism. Although many skeletal muscle proteins are O-GlcNAcylated, the modification has not been extensively studied in this tissue, especially in the context of exercise. This study investigated the effects of glutathione depletion and acute exercise on O-GlcNAc protein modification in rat skeletal muscle. Diethyl maleate (DEM) was used to deplete intracellular glutathione and rats were subjected to a treadmill run. White gastrocnemius and soleus muscles were analyzed for glutathione status, O-GlcNAc and O-GlcNAc transferase (OGT) protein levels, and mRNA expression of OGT, O-GlcNAcase and glutamine:fructose-6-phosphate amidotransferase. DEM and exercise both reduced intracellular glutathione and increased O-GlcNAc. DEM upregulated OGT protein expression. The effects of the interventions were significant 4 h after exercise (P < 0.05). The changes in the mRNA levels of O-GlcNAc enzymes were different in the two muscles, potentially resulting from different rates of oxidative stress and metabolic demands between the muscle types. These findings indicate that oxidative environment promotes O-GlcNAcylation in skeletal muscle and suggest an interrelationship between cellular redox state and O-GlcNAc protein modification. This could represent one mechanism underlying cellular adaptation to oxidative stress and health benefits of exercise.

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Section: Mrna Expression Of the O-glcnac Cycling Enzymesmentioning

confidence: 66%

Glutathione depletion and acute exercise increase O-GlcNAc protein modification in rat skeletal muscle

et al. 2014

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“…The recent reports (21,23,28) and the present study about increased O-GlcNAcylation under glucose deprivation are interesting in a more general sense because they demonstrate a high degree of diversity. The mechanism leading to increased O-GlcNAcylation under glucose deprivation not only seems to vary in a cell type but also in a metabolism-related manner, which suggests that further studies on the regulation O-GlcNAcylation are warranted because of its importance for cellular function.…”

Section: Discussionmentioning

confidence: 93%

“…Although certain details of the mechanism leading to increased O-GlcNAcylation upon glucose deprivation are now established (21,23,28), the origin of the UDP-GlcNAc required for increased O-GlcNAcylation is unknown. Our results indicate that glycogen provides an important source for the needed glucose because the inhibition of GP, the rate-limiting enzyme for glycogenolysis, prevented increased O-GlcNAcylation under glucose deprivation.…”

Section: Discussionmentioning

confidence: 99%

“…7A). Recently, Taylor et al (23) reported no increase in AMPK pathway activation in glucose-deprived HepG2 cells. Furthermore, we observed that Compound C reduced the amount of glycogen synthase but not of GP (Fig.…”

Section: Increased O-glcnacylation In Response To Glucose Deprivationmentioning

confidence: 99%

“…Further studies have revealed the dynamics of O-GlcNAcylation in HepG2 cells during glucose deprivation and have shown that up-regulation of OGT is mediated by decreased HBP flux (23). In light of the above mentioned importance of glucose as a source for UDP-GlcNAc synthesis and thus protein O-GlcNAcylation, increased O-GlcNAcylation under glucose deprivation appears paradoxical.…”

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confidence: 99%

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O-GlcNAc Protein Modification in Cancer Cells Increases in Response to Glucose Deprivation through Glycogen Degradation

Kang

Park

et al. 2009

Journal of Biological Chemistry

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Although the level of O-GlcNAc transferase was unchanged, the enzyme contained less O-GlcNAc, and its activity was increased. Moreover, O-GlcNAcase activity was reduced. The studied cells contain glycogen, and we show that its degradation in response to glucose deprivation provides a source for UDP-GlcNAc required for increased O-GlcNAcylation under this condition. This required active glycogen phosphorylase and resulted in increased glutamine:fructose-6-phosphate amidotransferase, the first and rate-limiting enzyme in the hexosamine biosynthetic pathway. Interestingly, glucose deprivation reduced the amount of phosphofructokinase 1, a regulatory glycolytic enzyme, and blocked ATP synthesis. These findings suggest that glycogen is the source for increased O-GlcNAcylation but not for generating ATP in response to glucose deprivation and that this may be useful for cancer cells to survive.

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Hepatocyte nuclear factor 1 alpha (HNF1A) regulates transcription of O‐GlcNAc transferase in a negative feedback mechanism

Zhang

Xie

et al. 2019

FEBS Letters

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O‐GlcNAc transferase (OGT)‐catalyzed protein O‐GlcNAcylation is implicated in diverse cellular events. In the present study, we report the regulation of ogt transcription by the hepatocyte nuclear factor 1 homologue A (HNF1A) in HEK293T cells. We first identified a core ogt promoter (−150 to +200 bp) and confirmed its binding to the transcription factor HNF1A. We found that HNF1A regulates ogt transcription in a time‐dependent manner and that O‐GlcNAcylation of HNF1A represses ogt transcription. Electron‐transfer dissociation based tandem mass spectrometry analysis revealed 14 O‐GlcNAc sites on HNF1A, six of which are predominantly modified, including Ser303/304, Ser471, Ser560 and Thr563/564. We further found that loss of O‐GlcNAcylation at Ser303/304 or Thr563/564 significantly elevates ogt transcription. These findings highlight a negative feedback mechanism for ogt transcription, which partially explains the homeostasis of cellular O‐GlcNAcylation.

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Up-regulation of O-GlcNAc Transferase with Glucose Deprivation in HepG2 Cells Is Mediated by Decreased Hexosamine Pathway Flux

Abstract: O-Linked N-acetylglucosamine (O-GlcNAc

Cited by 93 publications

References 29 publications

Glutathione depletion and acute exercise increase O-GlcNAc protein modification in rat skeletal muscle

Glutathione depletion and acute exercise increase O-GlcNAc protein modification in rat skeletal muscle

O-GlcNAc Protein Modification in Cancer Cells Increases in Response to Glucose Deprivation through Glycogen Degradation

Hepatocyte nuclear factor 1 alpha (HNF1A) regulates transcription of O‐GlcNAc transferase in a negative feedback mechanism

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