Apoptotic Response through a High Mobility Box 1 Protein-Dependent Mechanism in LPS/GalN-Induced Mouse Liver Failure and Glycyrrhizin-Mediated Inhibition

Abstract

HMGB1 is a nuclear component involved in nucleosome stabilization and transcription regulation, but extracellularly it is able to serve as a potential late mediator of lethality. In the present study, we explored inflammation-promoting activity of HMGB1 and blockade of extracellular release of HMGB1 by glycyrrhizin (GL) in LPS/GalN-triggered mouse liver injury. At 1 to 10 h after LPS/GalN-treatment, mice were anesthetized to collect blood from heart puncture, and serum transaminase and HMGB1 were evaluated. Administration of LPS/GalN precipitated tissue injury associated with time-dependent alteration in HMGB1 serum levels. At 8 h nuclear immunoreactive products were remarkably reduced and extracellular HMGB1 expression was found exclusively in the pericentral foci. The treatment with GL significantly down-regulated the serum levels of ALT, AST, and HMGB1 in addition to the strong inhibition of tissue injury and extracellular immunoreactivity to HMGB1 and to acetylated-lysine. Furthermore, GL brought about a significant decrease in the number of apoptotic hepatocytes labeled with TUNEL-method. On the basis of these results, three apoptosis-associated genes were identified with microarray analysis and real-time PCR. The ChIP-assay revealed the binding of HMGB1 protein to Gsto1 promoter sequence in LPS/GalN-treated mice and the remarkable decrease in combined HMGB1 protein by GL. The current findings claim that a single injection of LPS/GalN might stimulate apoptosis of hepatocytes through the binding of HMGB1 protein to Gsto1 promoter region and that GL-treatment might prevent the apoptosis and inflammatory infiltrates caused with LPS/GalN-injection by disturbing the binding of HMGB1 protein to Gsto1 promoter sequence.

Nobiletin attenuates lipopolysaccharide/D-galactosamine-induced liver injury in mice by activating the Nrf2 antioxidant pathway and subsequently inhibiting NF-κB-mediated cytokine production

“…Therefore, there is an urgent need to develop novel drugs to control this condition. Lipopolysaccharide (LPS)-and D-galactosamine (GalN)-induced acute liver injury in mice is a well-established animal model that may accurately represent clinical symptoms in humans (4). It is widely used to investigate the underlying mechanisms and potential therapies for ALF.…”

“…It is widely used to investigate the underlying mechanisms and potential therapies for ALF. GalN is a specific hepatotoxic agent that inhibits RNA and protein synthesis in hepatocytes (4). LPS induces the production of inflammatory cytokines, resulting in subsequent liver tissue injury (5).…”

Novel Mechanism Supporting Therapeutic Effects of Glycyrrhizin in Acute or Chronic Hepatitis

“…We provide in vivo evidence showing that HMGB1 is involved in the apoptosis of hepatocytes caused by LPS/GalN-treatment and administration of GL signiicantly improves hepatic injury, in parallel with suppression of exaggerated apoptotic cell death and enhanced expression of regeneration mediator. Several recent investigations including our research [40] have reported that GL may protect against liver injury by reducing the expression of HMGB1, a mediator of inlammation [41,42]. The induction of liver injury in mice by LPS/GalN represents a promising animal model for elucidating the mechanism of clinical dysfunction and for evaluating the eicacy of hepatoprotectives.…”

The epithelial barrier and immunoglobulin A system in allergy

“…In ovalbumin‐induced experimental asthma, HMGB1 expression is increased, and addition of exogenous HMGB1 increased Th2 cells and levels of IL‐4, IL‐5, IL‐6, IL‐8 and IL‐17 . In addition, the blockade of HMGB1 binding to Gsto1 promoter region by glycyrrhizin in LPS/GalN‐triggered liver‐injured mice prevented apoptosis and inflammatory infiltrates . In HDM‐sensitized RAGE −/− mice, blockade of the HMGB1 downstream pathway strongly reduced Th2 responses .…”