HMGB1 promotes ductular reaction and tumorigenesis in autophagy-deficient livers
Bilon Khambu, … , Zheng Dong, Xiao-Ming Yin
Bilon Khambu, … , Zheng Dong, Xiao-Ming Yin
Published March 20, 2018
Citation Information: J Clin Invest. 2018;128(6):2419-2435. https://doi.org/10.1172/JCI91814.
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Research Article Cell biology Hepatology

HMGB1 promotes ductular reaction and tumorigenesis in autophagy-deficient livers

Abstract

Autophagy is important for liver homeostasis, and the deficiency leads to injury, inflammation, ductular reaction (DR), fibrosis, and tumorigenesis. It is not clear how these events are mechanistically linked to autophagy deficiency. Here, we reveal the role of high-mobility group box 1 (HMGB1) in two of these processes. First, HMGB1 was required for DR, which represents the expansion of hepatic progenitor cells (HPCs) implicated in liver repair and regeneration. DR caused by hepatotoxic diets (3,5-diethoxycarbonyl-1,4-dihydrocollidine [DDC] or choline-deficient, ethionine-supplemented [CDE]) also depended on HMGB1, indicating that HMGB1 may be generally required for DR in various injury scenarios. Second, HMGB1 promoted tumor progression in autophagy-deficient livers. Receptor for advanced glycation end product (RAGE), a receptor for HMGB1, was required in the same two processes and could mediate the proliferative effects of HMBG1 in isolated HPCs. HMGB1 was released from autophagy-deficient hepatocytes independently of cellular injury but depended on NRF2 and the inflammasome, which was activated by NRF2. Pharmacological or genetic activation of NRF2 alone, without disabling autophagy or causing injury, was sufficient to cause inflammasome-dependent HMGB1 release. In conclusion, HMGB1 release is a critical mechanism in hepatic pathogenesis under autophagy-deficient conditions and leads to HPC expansion as well as tumor progression.

Authors

Bilon Khambu, Nazmul Huda, Xiaoyun Chen, Yong Li, Guoli Dai, Ulrike A. Köhler, Wei-Xing Zong, Satoshi Waguri, Sabine Werner, Tim D. Oury, Zheng Dong, Xiao-Ming Yin

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Figure 6

HMGB1 release is an early event following loss of autophagy function.

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HMGB1 release is an early event following loss of autophagy function. (A...
(A) Atg7Hep-ERT2 mice were given tamoxifen on days 1 and 2. Livers were removed at different time points (days 5–20) and analyzed by immunoblot assay. Mice in the day 0 group received the vehicle control. (B) Densitometric levels of ATG7, HMGB1, NQO1, and p62 were normalized to GAPDH levels and to the day 0 control group. (C) Liver sections from Atg7Hep-ERT2 mice at different time points after induction were stained for HMGB1. Arrows indicate HMGB1-negative nuclei in hepatocytes. Scale bars: 10 μm. (D) Serum HMGB1 levels were determined in Atg7Hep-ERT2 mice from day 0 to day 30 after tamoxifen treatment. Significance was compared with day 0 (n = 4 mice/group). Insert shows the negative correlation of serum HMGB1 level with that of hepatic HMGB1 (from B). (E) Liver/body weight ratio (LW/BW) and serum ALT level were determined after tamoxifen treatment (n = 3 mice/group). Only statistically significantly different data are labelled with the asterisk (compared with day 0). (F) Liver sections from Atg7Hep-ERT2 mice at different time points after induction were H&E stained. Original magnification, ×400. (G and H) The number of hepatic CK19+ (G) and A6+ (H) cells was quantified in Atg7Hep-ERT2 mice at different time points after induction (n = 3 mice/group). See also the images in Supplemental Figure 12, E–F. (I) The number of hepatic CK19+ or SOX9+ cells was quantified in the indicated mice on days 0 and 50 after induction (n = 3 mice/group). See also the images in Supplemental Figure 12G. Data represent the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001, by 1-way ANOVA with Duncan’s post hoc analysis. D0, day 0; D5, day 5, etc.