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Aop: 285

AOP Title

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Inhibition of N-linked glycosylation leads to liver injury

Short name:

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Inhibition of N-linked glycosylation leads to liver injury

Graphical Representation

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Click to download graphical representation template

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Authors

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Huan Yangh, Kirsten E Snijders, Marije Niemeijer

Point of Contact

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Marvin Martens   (email point of contact)

Contributors

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  • Marvin Martens

Status

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Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite


This AOP was last modified on March 06, 2019 07:32

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Revision dates for related pages

Page Revision Date/Time
Inhibition of N-linked glycosylation March 06, 2019 07:44
Accumulation of misfolded proteins March 06, 2019 07:49
Unfolded Protein Response March 07, 2019 09:47
Apoptosis November 26, 2018 01:12
Activation of hepatic stellate cells March 06, 2019 07:50
Increased, Liver Steatosis March 07, 2019 09:49
Liver Injury March 07, 2019 04:23
Inhibition of N-linked glycosylation leads to Accumulation, misfolded proteins March 06, 2019 08:07
Accumulation, misfolded proteins leads to Unfolded Prortein Response March 06, 2019 08:06
Unfolded Prortein Response leads to Apoptosis March 06, 2019 08:09
Apoptosis leads to Activation, hepatic stellate cells March 06, 2019 08:10
Activation, hepatic stellate cells leads to Liver Injury March 06, 2019 08:10
Apoptosis leads to Liver Injury March 06, 2019 08:11

Abstract

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The Endoplasmic Reticulum (ER) is responsible for protein synthesis and folding making it the main target for the unfolded protein response (UPR). Cell stress can induce an increase in misfolded proteins that lead to the activation of the UPR through upregulation of sensors, transcription factors and downstream targets to recover homeostasis and control the levels of unfolded proteins in the ER. This adverse outcome pathway (AOP) outlines the way in which inhibition of N-linked glycosylation activates and disrupts the UPR leading to livery injury. It will provide more in depth knowledge on the thresholds involved during the UPR for the maintenance of homeostasis and the induction of the adverse outcome on the target organ of the Liver.

All newly synthesized proteins undergo glycosylation before they are folded in the ER. Any misfolding of proteins is resolved by the ER- associated degradation (ERAD) that recognizes and clears misfolded proteins from the ER. This quality control of protein folding is glycosylation directed. Misfolded proteins that are not N-linked glycosylated fail to be recognized by the ERAD.

The molecular initiating event for this AOP is the inhibition of N-linked glycosylation. This can be achieved through directly inhibiting either the biosynthesis or the processing of N-linked oligosaccharide chains. Enzymes that synthesize N-linked oligosaccharide chain are often targets for inhibition of glycosylation. Unglycosylated misfolded proteins are unable to be recognized or cleared by the ERAD thus leading to key event 1, a buildup of misfolded proteins. This accumulation activates sensors and triggers key event 2: the (UPR).

Whilst the UPR is in place to maintain homeostasis and resolve the buildup of misfolded proteins in the ER. The activation of the UPR coupled with an inability to resolve the buildup of misfolded protein, through compromised ERAD clearance, leads to key event 3: apoptosis of hepatocytes, triggered by UPR downstream target CHOP. This in turn will lead to the adverse outcome: Liver Injury.


Background (optional)

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Summary of the AOP

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Events: Molecular Initiating Events (MIE)

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Key Events (KE)

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Adverse Outcomes (AO)

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Sequence Type Event ID Title Short name
1 MIE 1604 Inhibition of N-linked glycosylation Inhibition of N-linked glycosylation
2 KE 1605 Accumulation of misfolded proteins Accumulation, misfolded proteins
3 KE 1512 Unfolded Protein Response Unfolded Prortein Response
4 KE 1262 Apoptosis Apoptosis
5 KE 1606 Activation of hepatic stellate cells Activation, hepatic stellate cells
6 KE 459 Increased, Liver Steatosis Increased, Liver Steatosis
7 AO 1549 Liver Injury Liver Injury

Relationships Between Two Key Events
(Including MIEs and AOs)

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Title Adjacency Evidence Quantitative Understanding
Inhibition of N-linked glycosylation leads to Accumulation, misfolded proteins adjacent Not Specified Not Specified
Accumulation, misfolded proteins leads to Unfolded Prortein Response adjacent Not Specified Not Specified
Unfolded Prortein Response leads to Apoptosis adjacent Not Specified Not Specified
Apoptosis leads to Activation, hepatic stellate cells adjacent Not Specified Not Specified
Activation, hepatic stellate cells leads to Liver Injury adjacent Not Specified Not Specified
Apoptosis leads to Liver Injury adjacent Not Specified Not Specified

Network View

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Stressors

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Life Stage Applicability

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Taxonomic Applicability

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Sex Applicability

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Overall Assessment of the AOP

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Domain of Applicability

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Essentiality of the Key Events

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Evidence Assessment

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Quantitative Understanding

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Considerations for Potential Applications of the AOP (optional)

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References

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