While foreign pathogens and their products have long been known to activate the innate immune system, the recent recognition of a group of endogenous molecules that serve a similar function has provided a framework for understanding the overlap between the inflammatory responses activated by pathogens and injury. These endogenous molecules, termed alarmins, are normal cell constituents that can be released into the extracellular milieu during states of cellular stress or damage and subsequently activate the immune system. One nuclear protein, High mobility group box-1 (HMGB1), has received particular attention as fulfilling the functions of an alarmin by being involved in both infectious and non-infectious inflammatory conditions. Once released, HMGB1 signals through various receptors to activate immune cells involved in the immune process. Although initial studies demonstrated HMGB1 as a late mediator of sepsis, recent findings indicate HMGB1 to have an important role in models of non-infectious inflammation, such as autoimmunity, cancer, trauma, and ischemia reperfusion injury. Furthermore, in contrast to its pro-inflammatory functions, there is evidence that HMGB1 also has restorative effects leading to tissue repair and regeneration. The complex functions of HMGB1 as an archetypical alarmin are outlined here to review our current understanding of a molecule that holds the potential for treatment in many important human conditions.

The mobilization and extracellular release of nuclear high mobility group box-1 (HMGB1) by ischemic cells activates inflammatory pathways following liver ischemia/reperfusion (I/R) injury. In immune cells such as macrophages, post-translational modification by acetylation appears to be critical for active HMGB1 release. Hyperacetylation shifts its equilibrium from a predominant nuclear location toward cytosolic accumulation and subsequent release. However, mechanisms governing its release by parenchymal cells such as hepatocytes are unknown. In this study, we found that serum HMGB1 released following liver I/R in vivo is acetylated, and that hepatocytes exposed to oxidative stress in vitro also released acetylated HMGB1. Histone deacetylases (HDACs) are a family of enzymes that remove acetyl groups and control the acetylation status of histones and various intracellular proteins. Levels of acetylated HMGB1 increased with a concomitant decrease in total nuclear HDAC activity, suggesting that suppression in HDAC activity contributes to the increase in acetylated HMGB1 release after oxidative stress in hepatocytes. We identified the isoforms HDAC1 and HDAC4 as critical in regulating acetylated HMGB1 release. Activation of HDAC1 was decreased in the nucleus of hepatocytes undergoing oxidative stress. In addition, HDAC1 knockdown with siRNA promoted HMGB1 translocation and release. Furthermore, we demonstrate that HDAC4 is shuttled from the nucleus to cytoplasm in response to oxidative stress, resulting in decreased HDAC activity in the nucleus. Together, these findings suggest that decreased nuclear HDAC1 and HDAC4 activities in hepatocytes following liver I/R is a mechanism that promotes the hyperacetylation and subsequent release of HMGB1. High Mobility Group Box Protein 1 (HMGB1)3 is a ubiquitously expressed nuclear molecule that functions as a structural protein of chromatin (1). In addition to its nuclear role, HMGB1 also functions as an inflammatory cytokine when released from necrotic cells or actively secreted from stressed cells. Its proinflammatory properties were first highlighted in experiments showing that HMGB1 is actively secreted by activated macrophages, serving as a late mediator of lethality in sepsis (2). Whereas HMGB1 is involved in the late systemic inflammatory response to sepsis, our laboratory demonstrated that HMGB1 is a central and necessary mediator of organ damage following acute, sterile organ injury (3, 4). HMGB1 is rapidly mobilized and released by hepatocytes in the setting of hepatic ischemia and reperfusion injury. Extracellular HMGB1 functions as a damage-associated molecular pattern (DAMP) molecule and activates proinflammatory signaling pathways by activating pattern recognition receptors including Toll-like receptor 4 (TLR4) and the receptor for advanced glycation end-products (RAGE) (5, 6). Mounting evidence suggests HMGB1 may also function to facilitate the recognition of other immune co-activators such as LPS, DNA, and IL-1 through avid binding to these molecules (7-9).Thoro...

Concomitant increasing incidences of hepatocellular carcinoma (HCC) and nonalcoholic steatohepatitis (NASH) suggest that a substantial proportion of HCC arises as a result of hepatocellular injury from NASH. The aim of this study was to determine differences in severity of liver dysfunction at HCC diagnosis and long-term survival outcomes between patients undergoing curative therapy for HCC in the background of NASH compared to hepatitis C virus (HCV) and/or alcoholic liver disease (ALD). Patient demographics and comorbidities, clinicopathologic data, and long-term outcomes among patients who underwent liver transplantation, hepatic resection, or radiofrequency ablation for HCC were reviewed. From 2000 to 2010, 303 patients underwent curative treatment of HCC; 52 (17.2%) and 162 (53.5%) patients had NASH and HCV and/or alcoholic liver disease. At HCC diagnosis, NASH patients were older (median age 65 versus 58 years), were more often female (48.1% versus 16.7%), more often had the metabolic syndrome (45.1% versus 14.8%), and had lower model for end-stage liver disease scores (median 9 versus 10) (all P < 0.05). NASH patients were less likely to have hepatic bridging fibrosis or cirrhosis (73.1% versus 93.8%; P < 0.001). After a median follow-up of 50 months after curative treatment, the most frequent cause of death was liver failure. Though there were no differences in recurrence-free survival after curative therapy (median, 60 versus 56 months; P 5 0.303), NASH patients had longer overall survival (OS) (median not reached versus 52 months; P 5 0.009) independent of other clinicopathologic factors and type of curative treatment. Conclusion: Patients with HCC in the setting of NASH have less severe liver dysfunction at HCC diagnosis and better OS after curative treatment compared to counterparts with HCV and/or alcoholic liver disease. (HEPATOLOGY 2012;55:1809-1819 C oncomitant increases in the incidence of hepatocellular carcinoma (HCC) and prevalence of nonalcoholic fatty liver disease (NAFLD) suggest that a substantial proportion of HCC arises as a result of hepatocellular injury from nonalcoholic steatohepatitis (NASH). As a result, HCC is the most rapidly increasing cause of cancer death in the United States.