TY - JOUR
T1 - HMGB1 promotes ductular reaction and tumorigenesis in autophagy-deficient livers
AU - Khambu, Bilon
AU - Huda, Nazmul
AU - Chen, Xiaoyun
AU - Antoine, Daniel J.
AU - Li, Yong
AU - Dai, Guoli
AU - Köhler, Ulrike A.
AU - Zong, Wei Xing
AU - Waguri, Satoshi
AU - Werner, Sabine
AU - Oury, Tim D.
AU - Dong, Zheng
AU - Yin, Xiao Ming
N1 - Funding Information:
We would like to thank Eugene B. Chang (University of Chicago and the Digestive Disease Research Core Center, Chicago, Illinois, USA, sponsored by NIDDKP30 DK42086) for the Hmgb1?Hep mice; Komatsu Masaaki (Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan) for the Atg7fl/fl mice; Pierre Chambon and Daniel Metzger (University of Strasbourg, Strasbourg, France) for the Alb-Cre-ERT2 mice; Wen-Xing Ding (University of Kansas Medical Center, Kansas City, USA) for the Atg5/Nrf2 mouse samples; and Valentina Factor (Laboratory of Chemical Carcinogenesis, NIH, Bethesda, Maryland, USA) for the A6 antibody. The CK19 monoclonal antibodies were obtained from the Developmental Studies Hybridoma Bank, created by the National Institute of Child Health and Human Development (NICHD), NIH, and maintained at the Department of Biology of The University of Iowa (Iowa City, Iowa, USA). This work was supported in part by NIH grants R01AA021751 and R21AA021450 (to XMY).
PY - 2018/6/1
Y1 - 2018/6/1
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI91814
DO - 10.1172/JCI91814
M3 - Article
C2 - 29558368
AN - SCOPUS:85048267292
SN - 0021-9738
VL - 128
SP - 2419
EP - 2435
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 6
ER -