The Role of HMGB1 in autophagy deficiency-induced liver pathology

HMGB1 在自噬缺陷引起的肝脏病理中的作用

• 批准号: 10188516
• 负责人: XIAO-MING YIN
• 金额: $ 40.04万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-26 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10188516
• 关键词: Address; Affect; Alcohols; Autophagocytosis; Biological; Biological Process; Cell Death; Cells; Chronic Disease; DNA-Binding Proteins; Development; Diet; Disease; Event; Fibrosis; Fostering; Growth Factor; HMGB1 gene; Hepatic; Hepatocyte; Hepatomegaly; Homeostasis; Inflammasome; Inflammation; Inflammatory; Injury; Lead; Life; Liver; Liver diseases; Liver neoplasms; MAP Kinase Gene; Modality; Molecular; Nuclear; Nutrient; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pattern; Play; Process; Reaction; Research; Role; Signal Pathway; Testing; Therapeutic; Tissues; Virus; Work; base; chronic liver disease; extracellular; injury and repair; insight; liver injury; macrophage; member; notch protein; novel; oval cell; receptor; receptor for advanced glycation endproducts; repaired; stem cells; tumor; tumor microenvironment; tumor progression; tumorigenesis

Macroautophagy, hereafter referred to as autophagy, is an evolutionarily conserved intracellular degradation mechanism involved in diverse biological activities and in the pathogenesis of many diseases. The homeostatic importance of autophagy for the liver is indicated in the fact that autophagy deficiency causes multiple liver pathologies, including hepatomegaly, injury, inflammation, ductular reaction, fibrosis and tumorigenesis. What are being triggered by autophagy deficiency to lead to these changes are largely unknown but understanding the involved mechanisms will provide the insight not only on how autophagy maintains hepatic homeostasis, but also on how similar processes occur in other chronic diseases, such as those caused by alcohol, hyper-nutrients, and hepatic viruses. Toward that end, we have found that HMGB1 is actively released from autophagy-deficient hepatocytes, which is different from the more commonly seen case of passive release from dead cells during injury, but is similar to the active release by macrophages during inflammation. Regulatory mechanisms including Nrf2 and Caspase1 affect HMGB1 release independently from liver injury. HMGB1 acts in an extracellular mode and requires its receptor, RAGE, to regulate the ductular reaction, i.e., the expansion of ductular cells (DRs), also known as hepatic progenitor cells (HPCs) or oval cells, and to promote the development of hepatic tumors. These results indicate that hepatic HMGB1 plays an important and unique role in the liver pathogenesis caused by autophagy deficiency. The proposal have three aims. In Aim 1 we will investigate the mechanism of HMGB1 release from hepatocytes, addressing the hypothesis that inflammasomes are involved in the process. In Aim 2 we will examine the mechanism of ductular reaction promoted by HMGB1. In Aim 3 we will dissect the mechanisms of HMGB1 in tumor progression by examining the hypothesis that HMGB1 may alter the hepatic microenvironment. The successful completion of this work will reveal the novel roles of hepatocyte-derived HMGB1 in hepatic homeostasis and the results may be generally applicable to similar pathogenic processes in other types of chronic liver diseases, thus advancing the research in this field.

巨自噬，以下简称自噬，是一种进化上保守的细胞内自噬。 降解机制涉及多种生物活动和许多疾病的发病机制， 疾病自噬对肝脏的稳态重要性表明， 自噬缺陷引起多种肝脏病理，包括肝肿大，损伤，炎症， 小管反应、纤维化和肿瘤发生。自噬缺陷会触发什么 导致这些变化的原因在很大程度上是未知的，但了解所涉及的机制将提供 这不仅是关于自噬如何维持肝脏稳态， 过程发生在其他慢性疾病，如酒精，营养过剩， 肝病毒 为此，我们发现HMGB1从自噬缺陷的细胞中主动释放， 肝细胞，这与更常见的从死细胞被动释放的情况不同 在损伤期间，但类似于炎症期间巨噬细胞的主动释放。监管 包括Nrf2和Caspase1的机制独立于肝损伤影响HMGB1的释放。 HMGB1以细胞外模式发挥作用，需要其受体β 1调节肾小管上皮细胞的增殖。 反应，即，导管细胞（DR）的扩增，也称为肝祖细胞（HPC）或 卵圆细胞，并促进肝肿瘤的发展。这些结果表明， HMGB 1在自噬缺陷引起的肝脏发病机制中发挥着重要而独特的作用。 该提案有三个目标。在目标1中，我们将研究HMGB1释放的机制， 从肝细胞，解决的假设，炎性小体参与的过程。在Aim中 2.我们将研究HMGB1促进小管反应的机制。在目标3中，我们将剖析 HMGB1在肿瘤进展中的机制，通过检验HMGB1可能改变肿瘤细胞的增殖和分化的假说， 肝脏微环境这部作品的成功完成将揭示出 肝细胞衍生的HMGB1在肝脏内稳态中的作用，结果可能普遍适用于 在其他类型的慢性肝病中类似的致病过程，从而推进了 该领域

项目成果

The Role of Extracellular Vesicles in Liver Pathogenesis.

• DOI: 10.1016/j.ajpath.2022.06.007
• 发表时间: 2022-06
• 期刊: The American journal of pathology
• 作者: Gang Liu;X. Yin

Hepatic Autophagy Deficiency Remodels Gut Microbiota for Adaptive Protection via FGF15-FGFR4 Signaling.

• DOI: 10.1016/j.jcmgh.2020.10.011
• 发表时间: 2021
• 期刊: Cellular and molecular gastroenterology and hepatology
• 影响因子: 7.2
• 作者: Yan S;Khambu B;Chen X;Dong Z;Guo G;Yin XM
• 通讯作者: Yin XM

NRF2 transcriptionally regulates Caspase-11 expression to activate HMGB1 release by Autophagy-deficient hepatocytes.

• DOI: 10.1038/s41420-023-01495-x
• 发表时间: 2023-07-28
• 期刊: CELL DEATH DISCOVERY
• 影响因子: 7
• 作者: Khambu, Bilon;Cai, Genxiang;Liu, Gang;Bailey, Niani Tiaye;Mercer, Arissa A. A.;Baral, Kamal;Ma, Michelle;Chen, Xiaoyun;Li, Yu;Yin, Xiao-Ming
• 通讯作者: Yin, Xiao-Ming

Autophagy in liver diseases: A matter of what to remove and whether to keep.

肝脏疾病中的自噬：去除什么以及是否保留的问题。

• DOI: 10.1016/j.livres.2018.09.001
• 发表时间: 2018
• 期刊: Liver research
• 作者: Yin,Xiao-Ming