PUBLICATION
Glutathione antioxidant pathway activity and reserve determine toxicity and specificity of the biliary toxin biliatresone in zebrafish
- Authors
- Zhao, X., Lorent, K., Wilkins, B., Marchione, D.M., Gillespie, K., Waisbourd-Zinman, O., So, J., Koo, K.A., Shin, D., Porter, J.R., Wells, R.G., Blair, I., Pack, M.
- ID
- ZDB-PUB-160423-5
- Date
- 2016
- Source
- Hepatology (Baltimore, Md.) 64(3): 894-907 (Journal)
- Registered Authors
- Lorent, Kristin, Pack, Michael, Shin, Donghun, So, Juhoon
- Keywords
- Biliary atresia, Nrf2, cholangiocytes, redox stress
- Datasets
- GEO:GSE76780
- MeSH Terms
-
- Acetylcysteine
- Animals
- Animals, Genetically Modified
- Benzodioxoles/toxicity*
- Biliary Atresia/chemically induced*
- Biliary Atresia/metabolism
- Disease Models, Animal
- Glutathione/metabolism*
- Hepatocytes/metabolism
- Isothiocyanates
- Kelch-Like ECH-Associated Protein 1/metabolism
- Liver/metabolism
- NF-E2-Related Factor 2/genetics
- NF-E2-Related Factor 2/metabolism*
- Oxidation-Reduction
- Zebrafish
- PubMed
- 27102575 Full text @ Hepatology
Citation
Zhao, X., Lorent, K., Wilkins, B., Marchione, D.M., Gillespie, K., Waisbourd-Zinman, O., So, J., Koo, K.A., Shin, D., Porter, J.R., Wells, R.G., Blair, I., Pack, M. (2016) Glutathione antioxidant pathway activity and reserve determine toxicity and specificity of the biliary toxin biliatresone in zebrafish. Hepatology (Baltimore, Md.). 64(3):894-907.
Abstract
Biliatresone is an electrophilic isoflavone isolated from Dysphania species plants that has been causatively linked to naturally occurring outbreaks of a biliary atresia (BA)-like disease in livestock. Biliatresone has selective toxicity for extrahepatic cholangiocytes (EHC) in zebrafish larvae. To better understand its mechanism of toxicity, we performed transcriptional profiling of liver cells isolated from zebrafish larvae at the earliest stage of biliatresone-mediated biliary injury, with subsequent comparison of biliary and hepatocyte gene expression profiles. Transcripts encoded by genes involved in redox stress response, particularly those involved in glutathione (GSH) metabolism, were among the most prominently upregulated in both cholangiocytes and hepatocytes of biliatresone-treated larvae. Consistent with these findings, hepatic GSH was depleted at the onset of biliary injury, and in situ mapping of the hepatic GSH redox potential using a redox-sensitive GFP (roGFP) biosensor showed that it was significantly more oxidized in EHC both before and after treatment with biliatresone. Pharmacological and genetic manipulation of GSH redox homeostasis confirmed the importance of GSH in modulating biliatresone-induced injury as GSH depletion sensitized both EHC and the otherwise resistant intrahepatic cholangiocytes (IHC) to the toxin, whereas replenishing GSH level via N-acetylcysteine administration or activation of nuclear factor, erythroid 2-like 2 (Nrf2), a transcriptional regulator of GSH synthesis, inhibited EHC injury.
Conclusion These findings strongly support redox stress as a critical contributing factor in biliatresone-induced cholangiocyte injury, and suggest variations in intrinsic stress responses underlie the susceptibility profile. Insufficient antioxidant capacity of EHC may be critical to the early pathogenesis of human BA.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping