HMGB1 promotes ductular reaction and tumorigenesis in autophagy-deficient livers
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
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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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 7

NRF2 is required for hepatic HMGB1 release and DR.

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NRF2 is required for hepatic HMGB1 release and DR. (A) Liver sections of...
(A) Liver sections of 9-week-old mice were H&E stained (original magnification, ×200) or stained for HMGB1. (B) Percentage of cells with nuclear HMGB1, serum levels of HMGB1, and number of CK19+ or SOX9+ cells (n = 3–9 mice/group). See Supplemental Figure 14D for images of CK19+ and SOX9+ staining. (C) WT mice were given the vehicle control or BM for different durations, and blood ALT levels were measured (n = 3–6 mice/group). Variations in ALT values for the control mice (50 days vs. 6 days and 30 days) were due to reagent lot changes. (D) WT mice were given the vehicle control or BM for different durations. Hepatic lysates were analyzed by immunoblot assay. (E) Liver sections of mice treated with BM or control for 6 days were stained as indicated. Arrows indicate hepatocytes without nucleus HMGB1. (F) Serum levels of HMGB1 (n = 3–9 mice/group). (G) Liver sections from mice receiving the 50-day treatment regime were H&E stained (original magnification, ×200) or immunostained for CK19. (H and I) Liver sections from mice of the indicated genotypes were H&E stained (original magnification, ×200) or immunostained for HMGB1 or CK19 (H). Yellow arrows indicate hepatocytes without nuclear HMGB1; white arrows indicate hepatocytes with cytosolic HMGB1. (I) Cells with nuclear HMGB1 were quantified (n = 3 mice/group). Scale bars: 10 μm (A and E) and 50 μm (G and H). Data represent the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001, by 1-way ANOVA (B) or Student’s t test (C, F, and I).