Journal of Physiology and Biochemistry

, Volume 74, Issue 2, pp 345–358 | Cite as

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


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.


Diabetes Ethyl pyruvate HMGB1/TLR4 signaling Inflammatory response Liver 


Funding information

This work was supported by the Ministry of Education, Science and Technological Development of the Republic of Serbia (Grant No. 173020).

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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