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AOP: 285

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

Inhibition of N-linked glycosylation leads to liver injury

Short name

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The current version of the Developer's Handbook will be automatically populated into the Handbook Version field when a new AOP page is created.Authors have the option to switch to a newer (but not older) Handbook version any time thereafter. More help

Handbook Version v2.0

Graphical Representation

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Click to download graphical representation template Explore AOP in a Third Party Tool

Authors

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Huan Yang, Kirsten E Snijders, Marije Niemeijer

Point of Contact

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Arthur Author (email point of contact)

Contributors

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Marvin Martens
Kirsten Snijders
Arthur Author

Coaches

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OECD Information Table

Provides users with information concerning how actively the AOP page is being developed and whether it is part of the OECD Workplan and has been reviewed and/or endorsed. OECD Project: Assigned upon acceptance onto OECD workplan. This project ID is managed and updated (if needed) by the OECD. OECD Status: For AOPs included on the OECD workplan, ‘OECD status’ tracks the level of review/endorsement of the AOP . This designation is managed and updated by the OECD. Journal-format Article: The OECD is developing co-operation with Scientific Journals for the review and publication of AOPs, via the signature of a Memorandum of Understanding. When the scientific review of an AOP is conducted by these Journals, the journal review panel will review the content of the Wiki. In addition, the Journal may ask the AOP authors to develop a separate manuscript (i.e. Journal Format Article) using a format determined by the Journal for Journal publication. In that case, the journal review panel will be required to review both the Wiki content and the Journal Format Article. The Journal will publish the AOP reviewed through the Journal Format Article. OECD iLibrary published version: OECD iLibrary is the online library of the OECD. The version of the AOP that is published there has been endorsed by the OECD. The purpose of publication on iLibrary is to provide a stable version over time, i.e. the version which has been reviewed and revised based on the outcome of the review. AOPs are viewed as living documents and may continue to evolve on the AOP-Wiki after their OECD endorsement and publication. More help

OECD Project #	OECD Status	Reviewer's Reports	Journal-format Article	OECD iLibrary Published Version

This AOP was last modified on May 26, 2024 20:39

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	September 14, 2023 08:51
Apoptosis	February 28, 2024 09:40
Activation of hepatic stellate cells	March 06, 2019 07:50
Increased, Liver Steatosis	May 21, 2024 10:00
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 Protein Response	March 06, 2019 08:06
Unfolded Protein 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.

AOP Development Strategy

Context

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Strategy

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Summary of the AOP

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Events:

Molecular Initiating Events (MIE)

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Key Events (KE)

A measurable event within a specific biological level of organisation. More help

Adverse Outcomes (AO)

An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help

Type	Event ID	Title	Short name

MIE

1604

Inhibition of N-linked glycosylation

KE	1605	Accumulation of misfolded proteins	Accumulation, misfolded proteins
KE	1512	Unfolded Protein Response	Unfolded Protein Response
KE	1262	Apoptosis	Apoptosis
KE	1606	Activation of hepatic stellate cells	Activation, hepatic stellate cells
KE	459	Increased, Liver Steatosis	Increased, Liver Steatosis

1549

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 Protein Response	adjacent	Not Specified	Not Specified
Unfolded Protein 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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Prototypical Stressors

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Life Stage Applicability

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Taxonomic Applicability

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Sex Applicability

The sex for which the AOP is known to be applicable. More help

Overall Assessment of the AOP

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Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

Evidence Assessment

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Known Modulating Factors

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Quantitative Understanding

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Considerations for Potential Applications of the AOP (optional)

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References

List of the literature that was cited for this AOP. More help