The transcription factor c-Jun protects against sustained hepatic endoplasmic reticulum stress thereby promoting hepatocyte survival

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)