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E-GEOD-54256 - Expression data from primary mouse hepatocytes treated with Diclofenac

Status
Released on 22 January 2014, last updated on 26 January 2014
Organism
Mus musculus
Samples (10)
Array (1)
Protocols (7)
Description
Drug-induced liver injury (DILI) is an important clinical problem. Here we used a genomics approach to establish the critical drug-induced toxicity pathways that act in synergy with the pro-inflammatory cytokine tumor necrosis factor  (TNF) to cause cell death of liver HepG2 cells. Transcriptomics of the cell injury stress response pathways initiated by two hepatoxicants, diclofenac and carbamazepine, revealed the endoplasmic reticulum (ER) stress/translational initiation signaling and Nrf2 antioxidant signaling as two major affected pathways, which was similar to that observed for the majority of ~80 DILI compounds in primary human hepatocytes. The ER stress was primarily related to PERK and ATF4 activation and subsequent expression of CHOP, which was all independent of TNFα signaling. Identical ATF4 dependent transcriptional programs were observed in primary human hepatocytes as well as primary precision cut human liver slices. Targeted RNA interference studies revealed that while ER stress signaling through IRE1α and ATF6 acted cytoprotective, activation of the ER stress protein kinase PERK and subsequent expression of CHOP was pivotal for the onset of drug/TNF-induced apoptosis. While inhibition of the Nrf2-dependent adaptive oxidative stress response enhanced the drug/TNF cytotoxicity, Nrf2 signaling did not affect CHOP expression. Both hepatotoxic drugs enhanced expression of the translational initiation factor EIF4A1, which was essential for CHOP expression and drug/TNF-mediated cell killing. Our data support a model in which enhanced drug-induced translation initiates PERK-mediated CHOP signaling in an EIF4A1 dependent manner, thereby sensitizing towards caspase-8-dependent TNF induced apoptosis. 4 biological replicates of Diclofenac and 6 biological replicates of vehicle. 46 hours after isolation, cells were exposed to either 300 µM DCF or the solvent DMSO for 24 hours.
Experiment type
transcription profiling by array 
Contacts
Bob van de Water, Bram Herpers, Erik Danen, Geny Groothuis, Giulia Benedetti, Hans de Bont, John Meerman, Lisa Fredriksson, Mackenzie Hadi, Marjo de Graauw, Mirjam Luijten, Steven Wink
MIAME
PlatformsProtocolsVariablesProcessedRaw
Files
Investigation descriptionE-GEOD-54256.idf.txt
Sample and data relationshipE-GEOD-54256.sdrf.txt
Raw data (1)E-GEOD-54256.raw.1.zip
Processed data (1)E-GEOD-54256.processed.1.zip
Array designA-GEOD-14996.adf.txt
Links