Contribution of O-GlcNAc modification of NF-kB p65 in attenuation of diabetes-induced haptoglobin expression in rat liver
Keywords:haptoglobin, gene expression, diabetes, NF-kB p65, O-linked-N-acetylglucosamine modification
- 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.
Tseng CF, Lin CC, Huang HY, Liu HC, Mao SJ. Antioxidant role of human haptoglobin. Proteomics. 2004;4(8):2221-8.
Wang Y, Kinzie E, Berger FG, Lim SK, Baumann H. Haptoglobin, an inflammation-inducible plasma protein. Redox Rep. 2001;6(6):379-85.
Jain S, Gautam V, Naseem S. Acute-phase proteins: As diagnostic tool. J Pharm Bioallied Sci. 2011;3(1):118-27.
Arambašić J, Mihailović M, Bogojević D, Ivanović-Matić S, Uskoković A, Poznanović G, Grigorov I. Haptoglobin and the inflammatory and oxidative status in experimental diabetic rats: antioxidant role of haptoglobin. J Physiol Biochem. 2013;69(1):45-58.
Marinković S, Baumann H. Structure, hormonal regulation, and identification of the interleukin 6 and dexamethasone responsive element of the rat haptoglobin gene. Mol Cell Biol. 1990;10:1573-83.
Grigorov I, Lazić T, Cvetković I, Milosavljević T, Petrović M. STAT3 involvement in the acute phase-related expression of the rat haptoglobin gene. Mol Biol Rep. 2000;27:81–6.
Grigorov I, Lazić T, Cvetković I, Milosavljević T, Petrović M. Opposite nuclear level and binding activity of STAT5b and STAT3 proteins with rat haptoglobin gene under normal and turpentine induced acute phase conditions. Mol Biol Rep. 2002;28:217-22.
Arambašić J, Poznanović G, Ivanović-Matić S, Bogojević D, Mihailović M, Uskoković A, Grigorov I. Association of the glucocorticoid receptor with STAT3, C/EBPß and the hormone responsive element within the rat haptoglobin gene promoter during the acute phase response. IUBMB Life. 2010;62(3):227-36.
Ozcan S, Andrali SS, Cantrell JE. Modulation of transcription factor function by O-GlcNAc modification. Biochim Biophys Acta. 2010;1799(5-6):353-64.
Yang X, Qian K. Protein O-GlcNAcylation: emerging mechanisms and functions. Nat Rev Mol Cell Biol. 2017;18(7):452-65.
Slawson C, Copeland RJ, Hart GW. O-GlcNAc signaling: a metabolic link between diabetes and cancer? Trends Biochem Sci. 2010;35(10):547-55.
Karunakaran U, Jeoung NH. O-GlcNAc modification: Friend or foe in diabetic cardiovascular disease. Korean Diabetes J. 2010;34(4):211-19.
Ma J, Hart GW. Protein O-GlcNAcylation in diabetes and diabetic complications. Expert Rev Proteomics. 2013;10(4):365-80.
Zachara NE, Hart GW. O-GlcNAc a sensor of cellular state: the role of nucleocytoplasmic glycosylation in modulating cellular function in response to nutrition and stress. Biochim Biophys Acta. 2004;1673(1-2):13-28.
Lingappan K. NF-κB in oxidative stress. Curr Opin Toxicol. 2018;7:81-6.
Huang B, Yang XD, Lamb A, Chen LF. Posttranslational modifications of NF-kappaB: another layer of regulation for NF-kappaB signaling pathway. Cell Signal. 2010;22(9):1282-90.
Golks A, Tran TT, Goetschy JF, Guerini D. Requirement for O-linked N-acetylglucosaminyltransferase in lymphocytes activation. EMBO J. 2007;26(20):4368-79.
James LR, Tang D, Ingram A, Ly H, Thai K, Cai L, Scholey JW. Flux through the hexosamine pathway is a determinant of nuclear factor kappaB-dependent promoter activation. Diabetes. 2002;51(4):1146-56.
Dinić S, Arambašić J, Mihailović M, Uskoković A, Grdović N, Marković J, Karadžić B, Poznanović G, Vidaković M. Decreased O-GlcNAcylation of the key proteins in kinase and redox signalling pathways is a novel mechanism of the beneficial effect of α-lipoic acid in diabetic liver. Br J Nutr. 2013;110(3):401-12.
Asayama K, Uchida N, Nakane T, Hayashibe H, Dobashi K, Amemiya S, Kato K, Nakazawa S. Antioxidants in the serum of children with insulin-dependent diabetes mellitus. Free Radic Biol Med. 1993;15(6):597-02.
Kadonaga JT, Tijan R. Affinity purification of sequence-specific DNA binding proteins. Proc Natl Acad Sci USA. 1986;83:5889-93.
Uskoković A, Dinić S, Mihailović M, Grdović N, Arambašić J, Vidaković M, Bogojević D, Ivanović-Matić S, Martinović V, Petrović M, Poznanović G, Grigorov I. STAT3/NF-κB interactions determine the level of haptoglobin expression in male rats exposed to dietary restriction and/or acute phase stimuli. Mol Biol Rep. 2012;39(1):167-76.
Paulson M, Pisharody S, Pan L, Guadagno S, Mui AL, Levy DE. Stat protein transactivation domains recruit p300/CBP through widely divergent sequences. J Biol Chem. 1999;274:25343-9.
Wen Z, Zhong Z, Darnell JE Jr. Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell. 1995;82(2):241-50.
Decker T, Kovarik P. Serine phosphorylation of STATs. Oncogene. 2000;19(21):2628-37.
Kim JH, Yoon MS, Chen J. Signal transducer and activator of transcription 3 (STAT3) mediates amino acid inhibition of insulin signaling through serine 727 phosphorylation. J Biol Chem. 2009;284(51):35425-32.
Jovanović Stojanov S, Martinović V, Bogojević D, Poznanović G, Petrović A, Ivanović Matić S, Grigorov I. Modulation of diabetes-related liver injury by the HMGB1/TLR4 inflammatory pathway. J Physiol Biochem.2018;74(2):345-58.
Issad T, Masson E, Pagesy P. O-GlcNAc modification, insulin signaling and diabetic complications. Diabetes Metab. 2010;36(6 Pt 1):423-35.
Hart GW, Housley MP, Slawson C. Cycling of O-linked beta-N-acetylglucosamine on nucleocytoplasmic proteins. Nature. 2007;446(7139):1017-22.
Myslicki JP, Belke DD, Shearer J. Role of O-GlcNAcylation in nutritional sensing, insulin resistance and in mediating the benefits of exercise. Appl Physiol Nutr Metab. 2014;39(11):1205-13.
Brimble S, Wollaston-Hayden EE, Teo CF, Morris AC, Wells L. The Role of the O-GlcNAc Modification in Regulating Eukaryotic Gene Expression. Curr Signal Transduct Ther. 2010;5(1):12-24.
Shaw P, Freeman J, Bovey R, Iggo R. Regulation of specific DNA binding by p53: evidence for a role for O-glycosylation and charged residues at the carboxy-terminus. Oncogene. 1996;12:921–30.
Lamarre-Vincent N, Hsieh-Wilson LC. Dynamic glycosylation of the transcription factor CREB: a potential role in gene regulation. J Am Chem Soc. 2003;125:6612–3.
Chang WC, Hung JJ. Functional role of post-translational modifications of Sp1 in tumorigenesis. J Biomed Sci. 2012;19(1):94.
Patel S, Santani D. Role of NF-kappa B in the pathogenesis of diabetes and its associated complications. Pharmacol Rep. 2009;61(4):595-03.
Samarghandian S, Azimi-Nezhad M, Farkhondeh T. Immunomodulatory and antioxidant effects of saffron aqueous extract (Crocus sativus L.) on streptozotocin-induced diabetes in rats. Indian Heart J. 2017;69(2):151-9.
Van Bogaert T, De Bosscher K, Libert C. Crosstalk between TNF and glucocorticoid receptor signaling pathways. Cytokine Growth Factor Rev. 2010;21(4):275-86.
Altonsy MO, Sasse SK, Phang TL, Gerber AN. Context-dependent cooperation between nuclear factor κB (NF-κB) and the glucocorticoid receptor at a TNFAIP3 intronic enhancer: a mechanism to maintain negative feedback control of inflammation. J Biol Chem. 2014;289(12):8231-9.
Yang Won, Park S, Nam H, Kim D, Kang J, Kang E, Kim Y, Lee H, Kim K, Cho J. NFκB Activation Is Associated with Its O-GlcNAcylation State under Hyperglycemic Conditions. PNAS of America 2008;105(45):17345-50.
Christian F, Smith EL, Carmody RJ. The Regulation of NF-κB Subunits by Phosphorylation. Cells. 2016;5(1):12.
Yang WH, Kim JE, Nam HW, Ju JW, Kim HS, Kim YS, Cho JW. Modification of p53 with O-linked N-acetylglucosamine regulates p53 activity and stability. Nat Cell Biol. 2006;8(10):1074-83.
Zhang X, Blenis J, Li HC, Schindler C, Chen-Kiang S. Requirement of serine phosphorylation for formation of STAT-promoter complexes. Science. 1995;267(5206):1990-4.
Yu Z, Kone BC. The STAT3 DNA-binding domain mediates interaction with NF-kappaB p65 and inducible nitric oxide synthase transrepression in mesangial cells. J Am Soc Nephrol. 2004;15(3):585-91.
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