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

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.

β‐Hydroxybutyrate exacerbates lipopolysaccharide/d‐galactosamine‐induced inflammatory response and hepatocyte apoptosis in mice

“…In agree with this opinion, the present study found that supplementation with BHB exacerbated LPS/ d ‐Gal‐induced liver injury. In addition, the present study found that supplementation with BHB enhanced LPS/ d ‐Gal‐induced inflammation, and several reports shown that treatment with anti‐inflammation agents prevented diabetes‐associated liver injury . Therefore, the proinflammatory activities of BHB might be involved in the development of diabetes‐associated liver injury.…”

Molecular insights into the multifaceted functions and therapeutic targeting of high mobility group box 1 in metabolic diseases

“…In the liver tissue of streptozotocin‐induced diabetic rats, HMGB1‐TLR4 signalling is activated, accompanied by the activation of MAPK (p38, ERK, JNK), NFκB‐p65 and JAK1/STAT3 signalling pathways, which contributes to systemic inflammation ( Figure 2C). 50 Hyperhomocysteinemia (HHcy) induces expression and secretion of HMGB1 in vascular endothelial cells, which is regulated by Neuropilin‐1 (NRP1)‐p38 MAPK axis 51 . Vascular endothelial cell inflammation and dysfunction are common complications of diabetes that is controlled by hyperglycaemia‐induced miR‐106 and subsequent induction of HMGB1 expression and inflammation 52 …”

The Cooperative Induction of CCL4 in Human Monocytic Cells by TNF-α and Palmitate Requires MyD88 and Involves MAPK/NF-κB Signaling Pathways

“…The growing evidence now supports that free fatty acids can activate inflammatory signaling through different mechanisms including activation of the innate immune toll-like receptors (TLRs) [23,24]. TLR4, a member of the family of pattern-recognition receptors, activates the innate immune response after interaction with pathogen-associated molecular patterns including lipids, proteins, lipoproteins and LPS, as well as damage-associated signals or alarmins, e.g., high-mobility group box-1 protein (HMGB1) [25,26]. Binding of cognate ligands to TLRs activates two types of intracellular signaling pathways: One that requires myeloid differentiation factor-88 (MyD88) as an adaptor protein or another that involves the Toll/interleukin-1 receptor (TIR) domain-containing adaptor protein inducing IFNβ (TRIF).…”