API

Relationship: 1867

Title

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Apoptosis leads to Activation, hepatic stellate cells

Upstream event

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Apoptosis

Downstream event

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Activation, hepatic stellate cells

Key Event Relationship Overview

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AOPs Referencing Relationship

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AOP Name Adjacency Weight of Evidence Quantitative Understanding
Inhibition of N-linked glycosylation leads to liver injury adjacent Not Specified Not Specified

Taxonomic Applicability

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Sex Applicability

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Life Stage Applicability

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Key Event Relationship Description

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Apoptosis in hepatocytes, leads to Kupffer cell activation and TGFβ1 expression. This in turn activates stellate cells and the activation of inflammation response.

Evidence Supporting this KER

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Biological Plausibility

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Empirical Evidence

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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

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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.

Quantitative Understanding of the Linkage

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Response-response Relationship

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Time-scale

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Known modulating factors

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Known Feedforward/Feedback loops influencing this KER

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Domain of Applicability

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References

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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