HMGB1 promotes ductular reaction and tumorigenesis in autophagy-deficient livers

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

Research output: Contribution to journalArticlepeer-review

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 highmobility group box 1 (HMGB1) in two of these processes. First, HMGB1 was required for DR, which represents the expansion of hepatic progenitor cells (HPC) implicated in liver repair and regeneration. DR caused by hepatic toxic diets (DDC or CDE) also depended on HMGB1, indicating that HMGB1 may be generally required for DR in various injury scenarios. Second, HMGB1 promoted tumor development 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 HMGB1's proliferative effects in isolated HPC. HMGB1 was released from autophagy-deficient hepatocytes independently of cellular injury, but depending on NRF2 and inflammasome, which was activated by NRF2. Pharmacological or genetic activation of NRF2 alone without disabling autophagy or causing injury was sufficient to cause inflammasomedependent HMGB1 release. In conclusion, HMGB1 release is a critical mechanism in hepatic pathogenesis under the autophagy deficient condition, which leads to HPC expansion but also tumor development.

Original languageEnglish
JournalJournal of Clinical Investigation
Early online date20 Mar 2018
DOIs
Publication statusE-pub ahead of print - 20 Mar 2018

Keywords

  • Journal Article

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