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Relationship: 1867
Title
Apoptosis leads to Activation, hepatic stellate cells
Upstream event
Downstream event
Key Event Relationship Overview
AOPs Referencing Relationship
AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding | Point of Contact | Author Status | OECD Status |
---|---|---|---|---|---|---|
Inhibition of N-linked glycosylation leads to liver injury | adjacent | Not Specified | Not Specified | Arthur Author (send email) | Under development: Not open for comment. Do not cite |
Taxonomic Applicability
Sex Applicability
Life Stage Applicability
Key Event Relationship Description
Apoptosis in hepatocytes, leads to Kupffer cell activation and TGFβ1 expression. This in turn activates stellate cells and the activation of inflammation response.
Evidence Collection Strategy
Evidence Supporting this KER
Biological Plausibility
Empirical Evidence
CHOP induced apoptosis of hepatocytes leads to activation of hepatic stellate cells (Campos et al., 2014)(Foufelle & Fromenty, 2016)(Iracheta-Vellve et al., 2016)(Zhang et al., 2016)(Guicciardi, Malhi, Mott, & Gores, 2013)
Uncertainties and Inconsistencies
This is a secondary effect of the apoptosis, which indirectly leads to livery injury through stellate cell activation, with the most likely injury being fibrosis.
Known modulating factors
Quantitative Understanding of the Linkage
Response-response Relationship
Time-scale
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
References
Campos, G., Schmidt-Heck, W., Ghallab, A., Rochlitz, K., Pietter, L., Medinas, D. B., … Godoy, P. (2014). The transcription factor CHOP, a central component of the transcriptional regulatory network induced upon CCl4 intoxication in mouse liver, is not a critical mediator of hepatotoxicity. Archives of Toxicology. https://doi.org/10.1007/s00204-014-1240-8
Foufelle, F., & Fromenty, B. (2016). Role of endoplasmic reticulum stress in drug-induced toxicity. Pharmacology Research & Perspectives. https://doi.org/10.1002/prp2.211
Guicciardi, M. E., Malhi, H., Mott, J. L., & Gores, G. J. (2013). Apoptosis and Necrosis in the Liver Maria. Comprehensive Physiology, 3(2), 977–1010. https://doi.org/10.1002/cphy.c120020.Apoptosis
Iracheta-Vellve, A., Petrasek, J., Gyongyosi, B., Satishchandran, A., Lowe, P., Kodys, K., … Szabo, G. (2016). Endoplasmic reticulum stress-induced hepatocellular death pathways mediate liver injury and fibrosis via stimulator of interferon genes. Journal of Biological Chemistry. https://doi.org/10.1074/jbc.M116.736991
Tamaki, N., Hatano, E., Taura, K., Tada, M., Kodama, Y., Nitta, T., … Uemoto, S. (2008). CHOP deficiency attenuates cholestasis-induced liver fibrosis by reduction of hepatocyte injury. American Journal of Physiology. Gastrointestinal and Liver Physiology, 294(2), G498-505. https://doi.org/10.1152/ajpgi.00482.2007
Zhang, Z., Li, B., Meng, X., Yao, S., Jin, L., Yang, J., … Ning, G. (2016). Berberine prevents progression from hepatic steatosis to steatohepatitis and fibrosis by reducing endoplasmic reticulum stress. Scientific Reports. https://doi.org/10.1038/srep20848