HMGB1 links chronic liver injury to progenitor responses and hepatocarcinogenesis
Celine Hernandez, … , Richard A. Friedman, Robert F. Schwabe
Celine Hernandez, … , Richard A. Friedman, Robert F. Schwabe
Published April 1, 2019; First published March 20, 2018
Citation Information: J Clin Invest. 2018;128(6):2436-2450. https://doi.org/10.1172/JCI91786.
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Research Article Hepatology

HMGB1 links chronic liver injury to progenitor responses and hepatocarcinogenesis

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.

Authors

Celine Hernandez, Peter Huebener, Jean-Philippe Pradere, Richard A. Friedman, Robert F. Schwabe

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Figure 5

Disulfide HMGB1, but not fully reduced HMGB1, upregulates CD133 and promotes progenitor/ductular proliferation.

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Disulfide HMGB1, but not fully reduced HMGB1, upregulates CD133 and prom...
(A) BMOL cells were treated with recombinant disulfide HMGB1 (2 μg/ml) and fully reduced HMGB1 (2 μg/ml) for the indicated durations, followed by analysis of Cd133 mRNA by qPCR. (B) Phospho-kinase screen in untreated and disulfide HMGB1–treated (0.5 μg/ml for 30 minutes) BMOL cells. (C) BMOL cells were treated with disulfide HMGB1 (0.5 μg/ml) and fully reduced HMGB1 (0.5 μg/ml) for the indicated durations, followed by Western blot analysis for phosphorylated and total Erk. (D) BMOL cells were pretreated with the MEK inhibitor UO126 (10 μM) for 30 minutes, followed by treatment with disulfide HMGB1 (0.5 μg/ml) and qPCR analysis of Cd133 mRNA. (E) Proliferation was determined by MTT assay in BMOL cells treated with disulfide HMGB1 (0.5 μg/ml) or fully reduced HMGB1 (0.5 μg/ml) for the indicated durations. (F) Cytokeratin 19 and p–histone H3 (Ser10) double-positive cells were detected by confocal microscopy in Hmgb1fl/fl (black bar) and Hmgb1Δhep (blue bar) mice fed a DDC diet (n = 6 and n = 9 mice, respectively), and then cells were quantified. (G) BMOL cells were preincubated with RAGE- and TLR4-blocking antibodies, TLR9 inhibitor, or the appropriate controls, followed by treatment with disulfide HMGB1 (0.05 μg/ml) for 15 minutes and p-Erk and Erk Western blot analysis. Data are expressed as the mean ± SEM. qPCR data are expressed as the fold induction compared with untreated cells, and proliferation is expressed as the fold increase compared with the 0-hour time point. *P < 0.05, **P < 0.01, and ***P < 0.001, by unpaired, 2-tailed t test. Scale bars: 100 μm.