Department of Medicine, Columbia University, New York, NY, USA.
Institute of Human Nutrition, Columbia University, New York, NY, USA.
Nat Rev Gastroenterol Hepatol. 2018 Dec;15(12):738-752. doi: 10.1038/s41575-018-0065-y.
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.
细胞死亡是一种基本的生物学范式，几乎控制着每种肝脏疾病状况的结局和长期后果。急性肝衰竭的特征是大量实质细胞丧失，但通常随后会完全恢复。相比之下，慢性肝病中的细胞死亡程度通常较低，但会导致长期的器官结构和功能改变，导致慢性肝细胞更新、免疫细胞募集和肝星状细胞激活。这些慢性细胞死亡反应导致肝纤维化、肝硬化和癌症的发生。显然，除了细胞凋亡，坏死性细胞死亡也是肝脏中一种高度相关的程序性细胞死亡形式。特定形式的程序性细胞死亡的差异化激活不仅可能影响肝脏疾病的结局，而且还为治疗干预提供了新的机会。在这里，我们总结了关于疾病特异性激活和程序性细胞死亡形式的作用、它们对反应特征的贡献及其检测的潜在分子机制和悬而未决的问题。我们重点关注细胞凋亡和坏死性细胞死亡在急性肝损伤、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，以及可能转化为临床应用的机会。
