肝脏细胞凋亡和坏死性凋亡：生死攸关的问题

StephenW

Apoptosis and necroptosis in the liver: a matter of life and death

    Robert F. Schwabe & Tom Luedde

Nature Reviews Gastroenterology & Hepatologyvolume 15, pages738–752 (2018) | Download Citation
Abstract

Cell death represents a basic biological paradigm that governs outcomes and long-term sequelae in almost every hepatic disease condition. Acute liver failure is characterized by massive loss of parenchymal cells but is usually followed by restitution ad integrum. By contrast, cell death in chronic liver diseases often occurs at a lesser extent but leads to long-term alterations in organ architecture and function, contributing to chronic hepatocyte turnover, the recruitment of immune cells and activation of hepatic stellate cells. These chronic cell death responses contribute to the development of liver fibrosis, cirrhosis and cancer. It has become evident that, besides apoptosis, necroptosis is a highly relevant form of programmed cell death in the liver. Differential activation of specific forms of programmed cell death might not only affect outcomes in liver diseases but also offer novel opportunities for therapeutic intervention. Here, we summarize the underlying molecular mechanisms and open questions about disease-specific activation and roles of programmed cell death forms, their contribution to response signatures and their detection. We focus on the role of apoptosis and necroptosis in acute liver injury, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH) and liver cancer, and possible translations into clinical applications.
Key points

    Cell death is a fundamental driver of liver disease progression to liver fibrosis, cirrhosis and hepatocellular carcinoma.

    Depending on the underlying disease entity, distinct forms of programmed cell death and cell death response pathways can be activated in the liver.

    Necroptosis is a new form of programmed cell death that is activated by the necrosome, which consists of the kinases receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and RIPK3 and the pseudokinase mixed lineage kinase domain-like protein (MLKL).

    Despite necroptosis being challenging to detect in vivo, there is accumulating evidence that this cell death form is a pathogenically relevant driver in several liver diseases that were associated with apoptosis.

    Necroptosis seems to be particularly important in nonalcoholic fatty liver disease, nonalcoholic steatohepatitis and liver cancer but does not contribute to acetaminophen toxicity or ischaemia–reperfusion injury.

    A better functional characterization of necroptosis in liver disease models might lead to novel therapeutic strategies that target necroptosis to prevent the progression and decompensation of chronic liver disease.

StephenW

肝脏细胞凋亡和坏死性凋亡：生死攸关的问题

    Robert F. Schwabe和Tom Luedde

Nature Reviews Gastroenterology＆Hepatologyvolume 15，pages738-752（2018）|下载引文
抽象

细胞死亡代表了一种基本的生物学范例，它可以控制几乎所有肝病患者的预后和长期后遗症。急性肝功能衰竭的特征是实质细胞大量丢失，但通常随后恢复原状。相比之下，慢性肝病中的细胞死亡通常在较小程度上发生，但导致器官结构和功能的长期改变，导致慢性肝细胞更新，免疫细胞的募集和肝星状细胞的活化。这些慢性细胞死亡反应有助于肝纤维化，肝硬化和癌症的发展。显而易见的是，除细胞凋亡外，坏死性凋亡是肝脏中程序性细胞死亡的高度相关形式。特定形式的程序性细胞死亡的差异激活可能不仅影响肝脏疾病的结果，而且还提供治疗干预的新机会。在这里，我们总结了潜在的分子机制和关于疾病特异性激活和程序性细胞死亡形式的作用的开放性问题，它们对响应特征的贡献及其检测。我们关注细胞凋亡和坏死性凋亡在急性肝损伤，非酒精性脂肪性肝病（NAFLD），非酒精性脂肪性肝炎（NASH）和肝癌中的作用，以及可能的临床应用翻译。
关键点

    细胞死亡是肝病进展为肝纤维化，肝硬化和肝细胞癌的根本原因。

    根据潜在的疾病实体，可以在肝脏中激活不同形式的程序性细胞死亡和细胞死亡反应途径。

    坏死性凋亡是一种新的程序性细胞死亡形式，由坏死因子激活，其由激酶受体相互作用的丝氨酸/苏氨酸蛋白激酶1（RIPK1）和RIPK3以及假激酶混合谱系激酶结构域样蛋白（MLKL）组成。

    尽管坏死性细胞凋亡在体内检测具有挑战性，但是有越来越多的证据表明，这种细胞死亡形式是与细胞凋亡相关的几种肝脏疾病中的病原相关驱动因素。

    坏死性凋亡在非酒精性脂肪性肝病，非酒精性脂肪性肝炎和肝癌中似乎特别重要，但对对乙酰氨基酚毒性或缺血再灌注损伤没有贡献。

    肝病模型中坏死性凋亡的更好的功能表征可能导致针对坏死性凋亡的新型治疗策略，以防止慢性肝病的进展和失代偿。