The Role of HMGB1 in autophagy deficiency-induced liver pathology

巨细胞自噬，以下称为自噬，是一种进化上保守的细胞内自噬。 降解机制参与多种生物学活动，并参与许多 疾病。自噬对肝脏的动态平衡重要性体现在以下事实上 自噬缺陷会导致多种肝脏病理，包括肝肿大、损伤、炎症、 胆管反应、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，但了解相关的机制将提供 这不仅是关于自噬如何维持肝脏动态平衡的洞见，也是关于如何相似的洞察力 这一过程也发生在其他慢性疾病中，例如由酒精、高营养素和 肝脏病毒。 为此，我们发现HMGB1主动从自噬缺陷中释放出来 肝细胞，这与更常见的从死亡细胞被动释放的情况不同 在损伤过程中，但类似于炎症期间巨噬细胞的主动释放。监管 包括Nrf2和Caspase1在内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RAGE来调节导管 反应，即导管细胞(DR)的扩张，也称为肝祖细胞(HPC)或 卵圆细胞，并促进肝脏肿瘤的发展。这些结果表明，肝脏 HMGB1在自噬缺陷所致的肝脏发病机制中起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的释放机制 来自肝细胞，解决了炎症体参与这一过程的假说。在AIM 2我们将探讨HMGB1促进胆管反应的机制。在目标3中，我们将剖析 从HMGB1可能改变假说看HMGB1在肿瘤进展中的作用机制 肝脏微环境。这部作品的成功完成将揭示出 肝细胞来源的HMGB1在肝脏内稳态中的作用，其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，从而促进了对 这块地。

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.