API

Relationship: 1869

Title

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Apoptosis leads to Liver Injury

Upstream event

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Apoptosis

Downstream event

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Liver Injury

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 of hepatocytes triggers liver injury

Evidence Supporting this KER

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Biological Plausibility

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Apoptosis of hepatocytes triggers liver injury

Empirical Evidence

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See (Vinken et al., 2013; Landesmann, 2016)

Hepatic injury through apoptotic body formation in guinea pigs treated with tunicamycin. (Finnie, Read and Swift, 2004)

Hepatic injury through cell death and inflamation activation

(Willy et al., 2015)

Steatosis in the liver as a result of apoptosis ((Chikka et al., 2013)(Zhang et al., 2011)(Lebeaupin et al., 2015)

ATF6 deficcient mice are unable to perform recovering UPR and induce liver steatosis (Yamamoto et al., 2010)

Uncertainties and Inconsistencies

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What type of injury do we see? Fibrosis or steatosis or necrosis?

Tunicamycin is linked to steatosis, but this might not due to inhibition of glycosylation but other targets. Not enough to say injury, need more quantatative human measurements.

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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Chikka, M. R. et al. (2013) ‘C/EBP homologous protein (CHOP) contributes to suppression of metabolic genes during endoplasmic reticulum stress in the liver’, Journal of Biological Chemistry, 288(6), pp. 4405–4415. doi: 10.1074/jbc.M112.432344.

Finnie, J. W., Read, S. H. and Swift, J. G. (2004) ‘Apoptosis in liver damage produced by tunicamycin.’, Australian veterinary journal, 82(1–2), pp. 87–90. doi: 10.1111/j.1751-0813.2004.tb14652.x.

Landesmann, B. (2016) ‘Adverse Outcome Pathway on Protein Alkylation Leading to Liver Fibrosis’, (2).

Lebeaupin, C. et al. (2015) ‘ER stress induces NLRP3 inflammasome activation and hepatocyte death’, Cell Death and Disease. Nature Publishing Group, 6(9), p. e1879. doi: 10.1038/cddis.2015.248.

Vinken, M. et al. (2013) ‘Development of an adverse outcome pathway from drug-mediated bile salt export pump inhibition to cholestatic liver injury’, Toxicological Sciences. doi: 10.1093/toxsci/kft177.

Willy, J. A. et al. (2015) ‘CHOP links endoplasmic reticulum stress to NF- B activation in the pathogenesis of nonalcoholic steatohepatitis’, Molecular Biology of the Cell. doi: 10.1091/mbc.E15-01-0036.

Yamamoto, K. et al. (2010) ‘Induction of Liver Steatosis and Lipid Droplet Formation in ATF6␣-Knockout Mice Burdened with Pharmacological Endoplasmic Reticulum Stress’, Molecular Biology of the Cell, 21, pp. 2975–2986. doi: 10.1091/mbc.E09.

Zhang, K. et al. (2011) ‘The unfolded protein response transducer IRE1Î ± prevents ER stress-induced hepatic steatosis’, EMBO Journal. Nature Publishing Group, 30(7), pp. 1357–1375. doi: 10.1038/emboj.2011.52.