Abstract
Cell death is a key driver of disease progression and carcinogenesis in chronic liver disease (CLD), highlighted by the well-established clinical correlation between hepatocellular death and risk for the development of cirrhosis and hepatocellular carcinoma (HCC). Moreover, hepatocellular death is sufficient to trigger fibrosis and HCC in mice. However, the pathways through which cell death drives CLD progression remain elusive. Here, we tested the hypothesis that high-mobility group box 1 (HMGB1), a damage-associated molecular pattern (DAMP) with key roles in acute liver injury, may link cell death to injury responses and hepatocarcinogenesis in CLD. While liver-specific HMGB1 deficiency did not significantly affect chronic injury responses such as fibrosis, regeneration, and inflammation, it inhibited ductular/progenitor cell expansion and hepatocyte metaplasia. HMGB1 promoted ductular expansion independently of active secretion in a nonautonomous fashion, consistent with its role as a DAMP. Liver-specific HMGB1 deficiency reduced HCC development in 3 mouse models of chronic injury but not in a model lacking chronic liver injury. As with CLD, HMGB1 ablation reduced the expression of progenitor and oncofetal markers, a key determinant of HCC aggressiveness, in tumors. In summary, HMGB1 links hepatocyte death to ductular reaction, progenitor signature, and hepatocarcinogenesis in CLD.
Highlights
Chronic liver disease (CLD) causes approximately 2 million deaths per year worldwide [1]
As the majority of morbidity and mortality from liver disease arises in patients with chronic liver disease (CLD), we sought to determine whether high-mobility group box 1 (HMGB1) may play a role in biological processes that contribute to key features of CLD, such as the induction of inflammation, fibrosis, regeneration, and ductular reactions
It is conceivable that dying hepatocytes might utilize damage-associated molecular pattern (DAMP) to trigger the regeneration of surviving hepatocytes or instruct cells from other compartments to respond to injury and initiate wound-healing responses
Summary
Chronic liver disease (CLD) causes approximately 2 million deaths per year worldwide [1]. Cirrhosis and HCC are strongly linked to CLD and chronic hepatocellular death [3]. An increased risk for cirrhosis and HCC development in patients with high ALT is seen in different types of liver diseases, suggesting that cell death is a common risk factor for the progression [3]. We tested the hypothesis that DAMPs provide a molecular link between chronic liver injury, maladaptive wound healing, and HCC development, focusing on high-mobility group box 1 (HMGB1), a DAMP with key roles in sterile inflammation following acute liver injury [41]. Our findings suggest that HMGB1 links hepatocyte injury to ductular reactions, hepatocyte metaplasia, and HCC development in CLD
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