Diet Restriction Inhibits Apoptosis and HMGB1 Oxidation and Promotes Inflammatory Cell Recruitment during Acetaminophen Hepatotoxicity

Abstract

Acetaminophen (APAP) overdose is a major cause of acute liver failure and serves as a paradigm to elucidate mechanisms, predisposing factors and therapeutic interventions. The roles of apoptosis and inflammation during APAP hepatotoxicity remain controversial. We investigated whether fasting of mice for 24 h can inhibit APAP-induced caspase activation and apoptosis through the depletion of basal ATP . We also investigated in fasted mice the critical role played by inhibition of caspasedependent cysteine 106 oxidation within high mobility group box-1 protein (HMGB1) released by ATP depletion in dying cells as a mechanism of immune activation. In fed mice treated with APAP, necrosis was the dominant form of hepatocyte death. However, apoptosis was also observed, indicated by K18 cleavage, DNA laddering and procaspase-3 processing. In fasted mice treated with APAP, only necrosis was observed. Inflammatory cell recruitment as a consequence of hepatocyte death was observed only in fasted mice treated with APAP or fed mice cotreated with a caspase inhibitor. Hepatic inflammation was also associated with loss in detection of serum oxidized-HMGB1. A significant role of HMGB1 in the induction of inflammation was confirmed with an HMGB1-neutralizing antibody. The differential response between fasted and fed mice was a consequence of a significant reduction in basal hepatic ATP, which prevented caspase processing, rather than glutathione depletion or altered APAP metabolism. Thus, the inhibition of caspase-driven apoptosis and HMGB1 oxidation by ATP depletion from fasting promotes an inflammatory response during drug-induced hepatotoxicity/liver pathology.

HMGB1 in health and disease

“…Acetaminophen overdose is a well-known cause of DILI (Lee, 2004). A number of animal and human studies have demonstrated that serum HMGB1 is a diagnosis and severity-assessment biomarker of acute liver injury induced by acetaminophen, as well as other drugs (Antoine et al, 2013; Antoine et al, 2012a; Antoine et al, 2010; Dragomir et al, 2011; Gong et al, 2010a; Yang et al, 2012g; Zhou et al, 2011c). HMGB1 release during acetaminophen-mediated liver injury impairs the innate immune response and accelerates the inflammatory response (Scaffidi et al, 2002; Wang et al, 2007a; Wang et al, 2013m).…”

The HMGB1-RAGE Inflammatory Pathway: Implications for Brain Injury-Induced Pulmonary Dysfunction

“…It is likely that this protein took the all-thiol form of HMGB1 as it had chemotactic qualities to recruit enterocytes, smooth muscle, and endothelial, and stem cells (32,51,74,81,99,121,131). During active inflammation the predominant form of HMGB1 is thought to be the disulfide bond C23 and C45 (disulfide-HMGB1); however, when inflammation begins to subside, HMGB1 is terminally oxidized at the cysteine residues rendering it biological inactive (oxidized-HMGB1) (6,121,135). Subsequently, an oxidizing environment following inflammation or injury may promote HMGB1 cytokine activity, instead of cellular repair by monocyte recruitment (121).…”

Inhibition of high-mobility group box 1 as therapeutic option in autoimmune disease

“…Anti-HMGB1 monoclonal antibody [29] Anti-HMGB1 polyclonal antibody [28] Box A antagonist [28,30] Nuclear retention [24,27] Endotoxemia Inhibition of HMBG-1 release [31] CLP Anti-HMGB1 monoclonal antibody [34] Glucan phosphate (nuclear sequestering of HMGB1) [ Ischemia-reperfusion (kidney) Nuclear retention [37] Anti-HMGB1 polyclonal antibody [39] Ischemia-reperfusion (intestine) Anti-HMGB1 polyclonal antibody [41] Hepatoxicity Anti-HMGB1 polyclonal antibody [42] Pain Systemic injection of glycyrrhizin (binds to HMGB1) [43] Anti-HMGB1 polyclonal antibody [44,45] Islet transplantation Anti-HMGB1 monoclonal antibody [46] Atherosclerosis Anti-HMGB1 monoclonal antibody [47] Ischemia (brain) siRNA for HMGB1 [48] Anti-HMGB1 monoclonal antibody [49] Brain injury/damage to the blood-brain barrier Box A antagonist [50] Anti-HMGB1 monoclonal antibody [51] Intestinal tissue damage Anti-HMGB1 polyclonal antibody, nuclear retention [52] CLP, cecal ligation and puncture.…”