High-Mobility Group Box-1 and Liver Disease

Abstract

High-mobility group box-1 (HMGB1) is a ubiquitous protein. While initially thought to be simply an architectural protein due to its DNA-binding ability, evidence from the last decade suggests that HMGB1 is a key protein participating in the pathogenesis of acute liver injury and chronic liver disease. When it is passively released or actively secreted after injury, HMGB1 acts as a damage-associated molecular pattern that communicates injury and inflammation to neighboring cells by the receptor for advanced glycation end products or toll-like receptor 4, among others. In the setting of acute liver injury, HMGB1 participates in ischemia/reperfusion, sepsis, and drug-induced liver injury. In the context of chronic liver disease, it has been implicated in alcoholic liver disease, liver fibrosis, nonalcoholic steatohepatitis, and hepatocellular carcinoma. Recently, specific posttranslational modifications have been identified that could condition the effects of the protein in the liver. Here, we provide a detailed review of how HMGB1 signaling participates in acute liver injury and chronic liver disease.

Figure 1

HMGB1 protein structure. HMGB1 has 215 amino acids and two NLS (NLS1 spanning from histidine 27 to lysine 43 and NLS2 spanning from alanine 178 to lysine 184). Cysteines that can undergo oxidation are written in red (C23 and C45 form a disulfide bond), lysines that can undergo acetylation are written in blue, and a serine that can undergo phosphorylation is written in purple. These posttranslational modifications have been found in liver disease.

Figure 2

HMGB1 localization and secretion. During normal cellular homeostasis, HMGB1 preferentially accumulates in the nucleus due to its two NLSs; however, it can shuttle bidirectionally between the nucleus and the cytoplasm by the nuclear pore complex. Passive release of HMGB1 typically occurs in injured, apoptotic, necroptotic, or necrotic cells, where damage to the plasma and nuclear membranes occurs. Because HMGB1 lacks a hydrophobic secretion signal peptide, it is actively secreted by secretory lysosomes. Acetylation of critical residues located in both NLSs precludes HMGB1 from re‐entering the nucleus; as a result, it builds up in the cytoplasm and is eventually secreted to the extracellular space.

Figure 3

HMGB1 receptors and signaling. HMGB1 signals through RAGE and TLR4 in numerous cell types. In the hepatocyte, HMGB1 signals through RAGE, activating p‐p38/p42/44 MAPK, pJNK, and c‐Jun. In HSCs, HMGB1 can signal to RAGE to activate first pMEK1/2, pERK1/2, and p‐c‐Jun and second PI3K and pAKT1/2/3 to increase collagen‐I. HMGB1 activates TLR4 on hepatocytes to signal by MyD88‐dependent pathways or through pJNK, p‐c‐Jun, p38 MAPK, pERK to activate NFκB. In Kupffer cells, HMGB1 signals through TLR4, resulting in activation of p38 MAPK, pJNK, and NFκB, leading to induction of IL‐1β and TNFα. Abbreviations: MAPK, mitogen‐activated protein kinase; pMEK, phospho‐mitogen‐activated protein kinase kinase.