Karakterizacija strukture i funkcije HMGB1 proteina u jetri pacova tokom eksperimentalno izazvanog dijabetesa tipa 1
Structural and functional characterization of HMGB1 protein in rat liver during experimentally-induced diabetes type 1
Doctoral thesis (Published version)
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Oxidative stress and chronic inflammation are considered to be the main causes of diabetic complications, one of which is liver damage. An important mediator of these processes may be the endogenous HMGB1 protein, when released into the extracellular environment from the necrotic, damaged or activated cells. As the HMGB1 role in diabetes was insufficiently studied, in this doctoral dissertation the contribution of HMGB1 to liver damage of streptozotocin-induced diabetic rats was investigated. It has been shown that the level of liver damage in diabetes correlates with the presence of extracellular HMGB1. In diabetic liver, this protein is structurally modified by acetylation, phosphorylation, and O-GlcNAc glycosylation, which correlates with its translocation from the nucleus to the cytoplasm and an increase in its presence in the liver and serum. Reduction of the level of extracellular HMGB1 by melatonin or ethyl pyruvate treatment of diabetic rats, shows that HMGB1 contributes to diabetic liver damage by maintaining a chronic inflammation, by lowering antioxidant defense and by reducing regeneration. Extracellular HMGB1 activates MAPK/NF-κB p65 and JAK1/STAT3 signaling pathways through interactions with the TLR4 receptor, thus contributing increased production of proinflammatory cytokines TNF-α and IL-6 and the acute-phase protein, haptoglobin. By stimulating the NF-κB p65 inflammatory pathway, HMGB1 acts negatively on the cytoprotective response of the diabetic liver, by disabling Nrf2 protein activity, which is responsible for reduction of inflammation and antioxidant enzymes production. Activated HMGB1/TLR4 axis reduces regenerative potential of the liver by increasing the presence of negative cell cycle regulators - proteins p53 and p21, and also by decreasing the level of cyclin D1. The obtained results indicate the complexity of HMGB1 protein action in diabetes and underlines the importance of preventing the release of HMGB1 or blockage of HMGB1/TLR4 axis in order to delay the occurrence of liver damage.
Keywords:HMGB1 protein; Diabetes; Liver; Oxidative stress; Structural modifications; Inflammation; Regeneration
Source:Universiy of Belgrade, Faculty of Biology, 2018, 1-169
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