Division of Biliary and Gastrointestinal Oncology, University Hospital Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen, 52074 Aachen, Germany.
Department of Pathology and Molecular Pathology, University of Zurich and University Hospital Zurich, 8091 Zurich, Switzerland.
Proc Natl Acad Sci U S A. 2021 Mar 23;118(12). doi: 10.1073/pnas.2007194118.
The c-Jun N-terminal kinase (JNK) signaling pathway mediates adaptation to stress signals and has been associated with cell death, cell proliferation, and malignant transformation in the liver. However, up to now, its function was experimentally studied mainly in young mice. By generating mice with combined conditional ablation of and in liver parenchymal cells (LPCs) (JNK1/2 mice; KO, knockout), we unraveled a function of the JNK pathway in the regulation of liver homeostasis during aging. Aging JNK1/2 mice spontaneously developed large biliary cysts that originated from the biliary cell compartment. Mechanistically, we could show that cyst formation in livers of JNK1/2 mice was dependent on receptor-interacting protein kinase 1 (RIPK1), a known regulator of cell survival, apoptosis, and necroptosis. In line with this, we showed that RIPK1 was overexpressed in the human cyst epithelium of a subset of patients with polycystic liver disease. Collectively, these data reveal a functional interaction between JNK signaling and RIPK1 in age-related progressive cyst development. Thus, they provide a functional linkage between stress adaptation and programmed cell death (PCD) in the maintenance of liver homeostasis during aging.
c-Jun N-末端激酶 (JNK) 信号通路介导对应激信号的适应，与肝脏中的细胞死亡、细胞增殖和恶性转化有关。然而，到目前为止，其功能主要在年轻小鼠中通过实验进行了研究。通过在肝实质细胞 (LPC) 中生成同时条件性缺失 和 的小鼠 (JNK1/2 小鼠; KO，敲除)，我们揭示了 JNK 通路在衰老过程中调节肝脏稳态中的功能。衰老的 JNK1/2 小鼠自发地发展出大的胆管囊肿，这些囊肿来源于胆管细胞区室。从机制上讲，我们可以证明 JNK1/2 小鼠肝脏中的囊肿形成依赖于受体相互作用蛋白激酶 1 (RIPK1)，RIPK1 是细胞存活、凋亡和坏死性凋亡的已知调节剂。与此一致的是，我们发现 RIPK1 在一组多囊肝病患者的人类囊肿上皮中过度表达。总之，这些数据揭示了 JNK 信号通路和 RIPK1 在与年龄相关的进行性囊肿发展中的功能相互作用。因此，它们为应激适应和程序性细胞死亡 (PCD) 在衰老过程中维持肝脏稳态之间提供了功能联系。
