Abstract
High-mobility group box 1 (HMGB1) is a highly abundant DNA-binding protein that can relocate to the cytosol or undergo extracellular release during cellular stress or death. HMGB1 has a functional versatility depending on its cellular location. While intracellular HMGB1 is important for DNA structure maintenance, gene expression, and autophagy induction, extracellular HMGB1 acts as a damage-associated molecular pattern (DAMP) molecule to alert the host of damage by triggering immune responses. The biological function of HMGB1 is mediated by multiple receptors, including the receptor for advanced glycation end products (RAGE) and Toll-like receptors (TLRs), which are expressed in different hepatic cells. Activation of HMGB1 and downstream signaling pathways are contributing factors in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), and drug-induced liver injury (DILI), each of which involves sterile inflammation, liver fibrosis, ductular reaction, and hepatic tumorigenesis. In this review, we will discuss the critical role of HMGB1 in these pathogenic contexts and propose HMGB1 as a bona fide and targetable DAMP in the setting of common liver diseases.
Highlights
High-mobility group box 1 (HMGB1) is a highly abundant DNA-binding protein that can relocate to the cytosol or undergo extracellular release during cellular stress or death
HMGB1-ablated newborn mice liver, such as in hepatocytes, does not cause a deleterious phenotype suggesting that the HMGB1 role die from hypoglycemia due to the impairment of the activation of gene expression by the glucocorticoid is more important during the embryonic development and its function could be substituted by some receptor
We recently reported the important role of HMGB1 in the expansion of ductular cells (DCs) in autophagy-deficient livers and in various toxic dietary models, such as 3,5-diethoxycarbonyl-1,4-dihydrocollidine–supplemented (DDC-supplemented) diet-fed mice, and choline-deficient, ethionine-supplemented (CDE) diet-fed mice [7]
Summary
Damage-associated molecular pattern (DAMPs), known as amphoterin, danger signals, or alarmins, are host intracellular (cytosolic or nuclear) biomolecules that are secreted, released, or exposed on the cellular surface by stressed or dying cells. High-mobility group box (HMGB1) is a key chromosomal non-histone protein regulating DNA structure by binding to and bending through the minor groove. HMGB1 is not present or is significantly reduced in the nucleus of some hepatic cells hepatic cells (Figure 1) [7]; the reason is unknown to date. Post-translational modification through the redox regulation critical cysteine residues plays a key role in the inter- and intra-cellular translocation of HMGB1. (see of critical cysteine residues a key role in on thethe interandof intra-cellular translocation of HMGB1 recent reviews [8,9] forplays detail). Cell surface-specific expression of HMGB1 could be related its function. Cell surface-specific expression of HMGB1 could be related to the active secretion process
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