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Activation, hepatic stellate cells leads to Liver Injury
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 Do not cite|
Life Stage Applicability
Key Event Relationship Description
Stellate cell activation produces alterations in the extracellular matrix composition which lead to liver injury
Evidence Supporting this KER
Apoptosis of hepatocytes from CHOP leads to Kupffer cell activation, which leads to induction of TGF-β1 expression. This in turn activates stellate cells and activation of inflammation response. This results in collagen accumulation and change in extracellular matrix composition in the liver causing fibrosis. (Vinken et al 2015, Ladesmann 2016) (Iracheta-Vellve et al., 2016)(Koo et al., 2016)(Guicciardi et al., 2013)
Uncertainties and Inconsistencies
Inflamation response, not direct key event.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Guicciardi, M. E. et al. (2013) ‘Apoptosis and Necrosis in the Liver Maria’, Comprehensive Physiology, 3(2), pp. 977–1010. doi: 10.1002/cphy.c120020.Apoptosis.
Iracheta-Vellve, A. et al. (2016) ‘Endoplasmic reticulum stress-induced hepatocellular death pathways mediate liver injury and fibrosis via stimulator of interferon genes’, Journal of Biological Chemistry. doi: 10.1074/jbc.M116.736991.
Koo, J. H. et al. (2016) ‘Endoplasmic Reticulum Stress in Hepatic Stellate Cells Promotes Liver Fibrosis via PERK-Mediated Degradation of HNRNPA1 and Up-regulation of SMAD2’, Gastroenterology. Elsevier, Inc, 150(1), p. 181–193.e8. doi: 10.1053/j.gastro.2015.09.039.