The transcription factor c-Jun protects against sustained hepatic endoplasmic reticulum stress thereby promoting hepatocyte survival
The transcription factor c-Jun protects against sustained hepatic endoplasmic reticulum stress thereby promoting hepatocyte survival
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DOI：
10.1002/hep.24699
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发表时间：
2012-02-01
期刊：
影响因子：
13.5
通讯作者：
Hasselblatt, Peter
中科院分区：
文献类型：
--
作者：
Fuest, Matthias;Willim, Karolina;Hasselblatt, Peter
由于肝病毒或错误折叠蛋白积累引起的内质网应激越来越被认为是炎症性、毒性和代谢性肝脏疾病发病机制的重要步骤。内质网应激导致包括JNK在内的多种细胞内信号通路的激活。AP-1（活化蛋白1）转录因子c-Jun是一个典型的JNK靶点，也是肝细胞存活、增殖和肝脏肿瘤发生的重要调节因子。由于c-Jun在内质网应激反应中的功能尚不清楚，我们在原代肝细胞和肝细胞特异性c-Jun敲除小鼠的肝脏中研究了这一问题。通过体外和体内的药物诱导内质网应激，可快速、强效地诱导c-Jun蛋白的表达。有趣的是，缺乏c-Jun的ER应激肝细胞由于ER扩张而表现出大量细胞质空泡化。这种表型与典型内质网应激信号通路的加剧和持续激活相关。此外，缺乏c-Jun的肝细胞持续内质网应激导致细胞损伤和凋亡增加。内质网应激也是巨噬的强诱导剂，巨噬是细胞质成分和细胞器自我降解的一种细胞保护机制。有趣的是，在缺乏c-Jun的肝细胞中，响应内质网应激的自噬体数量减少。为了进一步验证这些发现，er应激野生型肝细胞的巨噬被化学抑制，导致细胞质空泡化和细胞损伤增加，与c- jun缺陷细胞的表型非常相似。结论：我们的研究结果表明，c-Jun保护肝细胞免受内质网应激反应的过度激活和随后的细胞死亡，并提供了c-Jun在功能上联系内质网应激反应和巨噬的证据。(肝脏病学2012)
Endoplasmic reticulum (ER) stress due to accumulation of hepatoviral or misfolded proteins is increasingly recognized as an important step in the pathogenesis of inflammatory, toxic, and metabolic liver diseases. ER stress results in the activation of several intracellular signaling pathways including Jun N-terminal kinase (JNK). The AP-1 (activating protein 1) transcription factor c-Jun is a prototypic JNK target and important regulator of hepatocyte survival, proliferation, and liver tumorigenesis. Because the functions of c-Jun during the ER stress response are poorly understood, we addressed this issue in primary hepatocytes and livers of hepatocyte-specific c-Jun knockout mice. ER stress was induced pharmacologically in vitro and in vivo and resulted in a rapid and robust induction of c-Jun protein expression. Interestingly, ER-stressed hepatocytes lacking c-Jun displayed massive cytoplasmic vacuolization due to ER distension. This phenotype correlated with exacerbated and sustained activation of canonical ER stress signaling pathways. Moreover, sustained ER stress in hepatocytes lacking c-Jun resulted in increased cell damage and apoptosis. ER stress is also a strong inducer of macroautophagy, a cell-protective mechanism of self-degradation of cytoplasmic components and organelles. Interestingly, autophagosome numbers in response to ER stress were reduced in hepatocytes lacking c-Jun. To further validate these findings, macroautophagy was inhibited chemically in ER-stressed wildtype hepatocytes, which resulted in cytoplasmic vacuolization and increased cell damage closely resembling the phenotypes observed in c-Jun-deficient cells. Conclusion: Our findings indicate that c-Jun protects hepatocytes against excessive activation of the ER stress response and subsequent cell death and provide evidence that c-Jun functionally links ER stress responses and macroautophagy. (HEPATOLOGY 2012)