The Transcription Factor c-Jun Protects Against Sustained Hepatic Endoplasmic Reticulum Stress Thereby Promoting Hepatocyte Survival

Abstract

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)

Excess iron modulates endoplasmic reticulum stress-associated pathways in a mouse model of alcohol and high-fat diet-induced liver injury

“…Current evidence suggests that JNK activation may promote cellular injury and apoptosis, but others have found that its induction may be a mechanism of cellular adaptive response to chronic stresses. 34 Given the role of IRE1a in preventing ER stress-induced hepatic steatosis, the suppression of JNK may reflect its role in nonapoptotic stress signaling responses in the development of hepatic injury secondary to iron, ethanol, and obesity. 35 To strengthen the argument for the role of iron in ER stress, we also examined pathways that are related to the UPR.…”

The transcription factor c-JUN/AP-1 promotes HBV-related liver tumorigenesis in mice

“…HBV replication and expression of hepatoviral proteins such as HBx strongly activate c-Jun. 3,[8][9][10] c-Jun is a member of the dimeric activator protein 1 (AP-1) transcription factor family, which mainly consists of Jun (c-Jun, JunB and JunD) and Fos proteins (cFos, FosB, Fra-1 and Fra-2). 11 c-Jun is expressed as an immediate early gene in response to a variety of stress stimuli, growth factors and subsequent signaling through MAP kinase pathways.…”

“…11 c-Jun is expressed as an immediate early gene in response to a variety of stress stimuli, growth factors and subsequent signaling through MAP kinase pathways. It is a major determinant of cell fate in the liver and regulates hepatocyte survival during acute hepatitis and ER stress 8,12 as well as hepatocyte proliferation following 2/3 partial hepatectomy. 13 Moreover, c-Jun acts as an oncogene in the liver and strongly promotes liver tumorigenesis in models of chemically induced HCC.…”

85 THE TRANSCRIPTION FACTOR c-JUN/AP-1 PROMOTES HBV-RELATED LIVER TUMORIGENESIS IN MICE

“…It is a major determinant of cell fate in the liver and regulates hepatocyte survival during acute hepatitis and ER stress 8,12 as well as hepatocyte proliferation following 2/3 partial hepatectomy. 13 Moreover, c-Jun acts as an oncogene in the liver and strongly promotes liver tumorigenesis in models of chemically induced HCC.…”

“…HBV replication and expression of hepatoviral proteins such as HBx strongly activate c-Jun. 3,[8][9][10] c-Jun is a member of the dimeric activator protein 1 (AP-1) transcription factor family, which mainly consists of Jun (c-Jun, JunB and JunD) and Fos proteins (cFos, FosB, Fra-1 and Fra-2).…”