Regulation of the hepatocellular response to endoplasmic reticulum stress by the transcription factor c-Jun/AP-1

Accumulation of viral or misfolded proteins in the endoplasmic reticulum (ER) and subsequent activation of cellular stress responses is an important step in the pathogenesis of inflammatory and metabolic liver disease. The transcription factor c-Jun/AP-1 regulates hepatocyte survival, proliferation and liver tumorigenesis, however, its functions during the ER stress response are incompletely understood and were addressed here using primary hepatocytes and livers from hepatocyte-specific c-Jun knockout mice (k.o.). ER stress was induced in vitro pharmacologically by Thapsigargin and Tunicamycin, respectively, and resulted in a robust induction of c-Jun expression. Interestingly, expression of various ER stress-related genes such as the pro-apoptotic transcription factor Gadd153, the ER resident chaperone Bip or splicing (i.e. activation) of the transcription factor XBP-1 was increased in k.o. hepatocytes. Moreover, signs of increased hepatocyte damage and cell death such as cytoplasmic vacuolization and ER swelling as determined by electron microscopy, cleavage of caspases 3, 7 and 12 and increased expression of the chemokines CXCL1 and CXCL2 were apparent in hepatocytes lacking c-Jun. Recent data suggest that autophagy, a conserved process of self-degradation of organelles, promotes cell survival during acute ER stress and is regulated by the Jun kinase JNK. Chemical inhibition of JNK or autophagy in ER-stressed wild-type hepatocytes also resulted in cytoplasmic vacuolization reminiscent of the phenotype observed in k.o. cells, in which autophagosome numbers were consistently reduced. Moreover, increased hepatic expression of ER stress related genes, cytoplasmic vacuolization and hepatocyte death were also apparent upon induction of ER stress in k.o. mice in vivo. These data suggest that c-Jun protects hepatocytes against excessive activation of the ER stress response and subsequent cell death, possibly by interacting with the autophagy machinery.

ER stress response - autophagy - hepatitis