Modulation of diabetes-related liver injury by the HMGB1/TLR4 inflammatory pathway

  • Sofija Jovanović Stojanov
  • Vesna Martinović
  • Desanka Bogojević
  • Goran Poznanović
  • Anja Petrović
  • Svetlana Ivanović-Matić
  • Ilijana Grigorov
Original Article
  • 58 Downloads

Abstract

Chronic inflammation plays an essential role in the development of diabetic complications. Understanding the molecular mechanisms that support inflammation is a prerequisite for the design of novel anti-inflammatory therapies. These would take into consideration circulating levels of cytokines and damage-associated molecular patterns (DAMPs) that include the high mobility group box 1 (HMGB1) protein which, in part, promotes the inflammatory response through TLR4 signaling. The liver, as the source of circulating cytokines and acute-phase proteins, contributes to the control of systemic inflammation. We previously found that liver injury in streptozotocin-induced diabetic rats correlated with the level of oxidative stress, increased expression of HMGB1, and with the activation of TLR4-mediated cell death pathways. In the present work, we examined the effects of ethyl pyruvate (EP), an inhibitor of HMGB1 release/expression, on the modulation of activation of the HMGB1/TLR4 inflammatory cascade in diabetic liver. We observed that increased expression of inflammatory markers, TNF-α, IL-6, and haptoglobin in diabetic liver was associated with increased HMGB1/TLR4 interaction, activation of MAPK (p38, ERK, JNK)/NF-κB p65 and JAK1/STAT3 signaling pathways, and with decreased expression of Nrf2-regulated antioxidative enzymes. The reduction in HMGB1 expression as the result of EP administration reduced the pro-inflammatory activity of HMGB1 and exerted a protective effect on diabetic liver, which was observed as improved liver histology and antioxidant and inflammatory statuses. Our results suggest that prevention of HMGB1 release and blockage of the HMGB/TLR4 axis represents a potentially effective therapeutic strategy aimed at ameliorating diabetes-induced inflammation and ensuing liver injury.

Keywords

Diabetes Ethyl pyruvate HMGB1/TLR4 signaling Inflammatory response Liver 

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© University of Navarra 2018

Authors and Affiliations

  • Sofija Jovanović Stojanov
    • 1
  • Vesna Martinović
    • 1
  • Desanka Bogojević
    • 1
  • Goran Poznanović
    • 1
  • Anja Petrović
    • 1
  • Svetlana Ivanović-Matić
    • 1
  • Ilijana Grigorov
    • 1
  1. 1.Department of Molecular Biology, Institute for Biological Research “Siniša Stanković”University of BelgradeBelgradeRepublic of Serbia

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