Contribution of O-GlcNAc modification of NF-kB p65 in attenuation of diabetes-induced haptoglobin expression in rat liver

Authors

  • Vesna I. Martinović Department of Molecular Biology, Institute for Biological Research “Siniša Stanković”, National Institute of the Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11060 Belgrade http://orcid.org/0000-0001-5916-9968
  • Jelena D. Arambašić Jovanović Department of Molecular Biology, Institute for Biological Research “Siniša Stanković”, National Institute of the Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11060 Belgrade http://orcid.org/0000-0002-8810-0668
  • Desanka B. Bogojević Department of Molecular Biology, Institute for Biological Research “Siniša Stanković”, National Institute of the Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11060 Belgrade http://orcid.org/0000-0003-1646-3846
  • Andjelija S. Ivanović Department of Molecular Biology, Institute for Biological Research “Siniša Stanković”, National Institute of the Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11060 Belgrade http://orcid.org/0000-0003-4807-5194
  • Vesna M. Otašević Department of Molecular Biology, Institute for Biological Research “Siniša Stanković”, National Institute of the Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11060 Belgrade http://orcid.org/0000-0001-8660-8284
  • Ana T. Stančić Department of Molecular Biology, Institute for Biological Research “Siniša Stanković”, National Institute of the Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11060 Belgrade http://orcid.org/0000-0003-0806-0799
  • Ilijana I. Grigorov Department of Molecular Biology, Institute for Biological Research “Siniša Stanković”, National Institute of the Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11060 Belgrade http://orcid.org/0000-0001-9540-4961

DOI:

https://doi.org/10.2298/ABS200928049M

Keywords:

haptoglobin, gene expression, diabetes, NF-kB p65, O-linked-N-acetylglucosamine modification

Abstract

Paper description:

  • Haptoglobin (Hp) is a hemoglobin-binding acute-phase protein with antiinflammatory and antioxidative properties. It was observed that an increase in Hp expression decreases diabetes progression.
  • The effects of O-GlcNAc modification of NF-kB p65 were investigated in the context of the formation of an effective transcription initiation complex on the Hp gene hormone-responsive element (HRE) during diabetes progression.
  • An increase in NF-κB p65 O-GlcNAcylation during the later stage of diabetes leads to disruption of NF-κB p65/STAT3, and consequently STAT3/GR interactions with HRE that contribute to decreased Hp expression.
  • O-GlcNAc could present a potential therapeutic strategy in diabetes management.

Abstract: Haptoglobin (Hp) is a hemoglobin-binding protein that prevents free hemoglobin-induced tissue oxidative damage. In streptozotocin-induced diabetic rats, the initial elevation of Hp expression in the serum and liver tends to decrease with diabetes progression, contributing to increased oxidative stress. Glucose toxicity and diabetic complications are closely related to increased modification of nucleocytoplasmic proteins by O-linked-N-acetylglucosamine (O-GlcNAc). We examined the contribution of O-GlcNAcylation of NF-kB p65 to changes in liver Hp expression in diabetic rats. WGA-affinity chromatography revealed a progressive increase in O-GlcNAcylation in nuclear NF-kB p65 during eight weeks of diabetes. DNA-affinity chromatography followed by immunoblot analysis revealed that decreased Hp expression at 4 and 8 weeks of diabetes was accompanied by the absence of Hp gene hormone-responsive element (HRE) occupancy with NF-kB p65, low occupancy with glucocorticoid receptor (GR), and almost no changes in STAT3 occupancy compared to 2 weeks, when Hp expression was highest. Coimmunoprecipitation experiments indicate that these events were the result of impaired NF-κB p65/STAT3 and GR/STAT3 interactions. Results suggest that the attenuation of Hp expression associated with diabetes was at least in part the result of O-GlcNAcylation of NF-κB p65, which prevents the formation of an effective transcription initiation complex on the Hp gene promoter.

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Published

2020-12-25

How to Cite

1.
Martinović VI, Arambašić Jovanović JD, Bogojević DB, Ivanović AS, Otašević VM, Stančić AT, Grigorov II. Contribution of O-GlcNAc modification of NF-kB p65 in attenuation of diabetes-induced haptoglobin expression in rat liver. Arch Biol Sci [Internet]. 2020Dec.25 [cited 2022Aug.7];72(4):555-6. Available from: https://www.serbiosoc.org.rs/arch/index.php/abs/article/view/5980

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