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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.

SUBMITTER: Khambu B

PROVIDER: S-EPMC5983330 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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

Khambu Bilon B Huda Nazmul N Chen Xiaoyun X Antoine Daniel J DJ Li Yong Y Dai Guoli G Köhler Ulrike A UA Zong Wei-Xing WX Waguri Satoshi S Werner Sabine S Oury Tim D TD Dong Zheng Z Yin Xiao-Ming XM

The Journal of clinical investigation 20180507 6

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 ( ...[more]

PMID: 29558368

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Project description:Mice with hepatocyte-specific deletion of autophagy-related 7 (Atg7 ΔHep mice) develop hepatoma, suggesting that autophagy deficiency could be a factor in the initiation of tumorigenesis. We have shown that FGF21 is induced as a 'mitokine' when Atg7 is disrupted in insulin target tissues such as the liver, which could affect systemic metabolism through endocrine activity. Since FGF21 or other endocrine FGF such as FGF19 can affect tumor growth, we hypothesized that FGF21 produced by Atg7-knockout (KO) hepatocytes may affect the behavior of Atg7-KO hepatoma in an autocrine manner. We, thus, crossed Atg7 ΔHep mice with systemic Fgf21-KO (Fgf21 -/-) mice to generate Atg7 ΔHep Fgf21 -/- mice. The number and size of hepatoma of Atg7 ΔHep mice were significantly increased by additional Fgf21 KO. The proliferation of Atg7-KO hepatocyte was significantly increased by Fgf21 KO. pYAP1/YAP1 representing YAP1 degradation was significantly decreased in the liver of Atg7 ΔHep Fgf21 -/- mice compared to Atg7 ΔHep Fgf21 +/+ mice. Consistently, expression of YAP1/TAZ downstream genes was significantly increased in the liver of Atg7 ΔHep Fgf21 -/- mice compared to Atg7 ΔHep Fgf21 +/+ mice, which could explain the increased size of hepatoma in Atg7 ΔHep Fgf21 -/- mice. Accumulation of ROS and ROS-mediated DNA damage were increased in the liver of Atg7 ΔHep Fgf21 +/+ mice, which was further aggravated by additional Fgf21 KO probably due to the absence of positive effect of FGF21 on mitochondrial function, explaining the increased number of hepatoma in Atg7 ΔHep Fgf21 -/- mice compared to Atg7 ΔHep Fgf21 +/+ mice. These results show that FGF21 produced by autophagy-deficient hepatocytes could have autocrine or paracrine effects on the number and proliferation of autophagy-deficient hepatoma, suggesting that hormones or factors released from autophagy-deficient tumors can influence the behavior or prognosis of the tumor in addition to the effects on host metabolism.

Project description:Background and objectivePersistent hepatic progenitor cells (HPC) activation resulting in ductular reaction (DR) is responsible for pathologic liver repair in cholangiopathies. Also, HPC/DR expansion correlates with fibrosis in several chronic liver diseases, including steatohepatitis. Increasing evidence indicates Notch signaling as a key regulator of HPC/DR response in biliary and more in general liver injuries. Therefore, we aimed to investigate the role of Notch during HPC/DR activation in a mouse model of steatohepatitis.MethodsSteatohepatitis was generated using methionine-choline deficient (MCD) diet. For hepatocyte lineage tracing, R26R-YFP mice were infected with AAV8-TBG-Cre.ResultsMCD diet promoted a strong HPC/DR response that progressively diffused in the lobule, and correlated with increased fibrosis and TGF-?1 expression. Notch signaling was unchanged in laser-capture microdissected HPC/DR, whereas Notch receptors were down regulated in hepatocytes. However, in-vivo lineage tracing experiments identified discrete hepatocytes showing Notch-1 activation and expressing (the Notch-dependent) Sox9. Stimulation of AML-12 hepatocyte-cell line with immobilized Jag1 induced Sox9 and down-regulated albumin and BSEP expression. TGF-?1 treatment in primary hepatic stellate cells (HSC) induced Jag1 expression. In MCD diet-fed mice, ?SMA-positive HSC were localized around Sox9 expressing hepatocytes, suggesting that Notch activation in hepatocytes was promoted by TGF-?1 stimulated HSC. In-vivo Notch inhibition reduced HPC response and fibrosis progression.ConclusionOur data suggest that Notch signaling is an important regulator of DR and that in steatohepatitis, hepatocytes exposed to Jag1-positive HSC, contribute to pathologic DR by undergoing Notch-mediated differentiation towards an HPC-like phenotype. Given the roles of Notch in fibrosis and liver cancer, these data suggest mesenchymal expression of Jag1 as an alternative therapeutic target.

Dataset Information

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

Publications

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

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