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
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
Inhibition of N-linked glycosylation leads to liver injury

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help
Click to download graphical representation template Explore AOP in a Third Party Tool
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Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

Huan Yang, Kirsten E Snijders, Marije Niemeijer

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Arthur Author   (email point of contact)

Contributors

Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Marvin Martens
  • Kirsten Snijders
  • Arthur Author

Status

Provides users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators. More help
Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite
This AOP was last modified on July 16, 2022 18:37

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 August 05, 2021 19:35
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

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

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

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

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Events:

Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
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 Inhibition of N-linked glycosylation
KE 1605 Accumulation of misfolded proteins Accumulation, misfolded proteins
KE 1512 Unfolded Protein Response Unfolded Prortein Response
KE 1262 Apoptosis Apoptosis
KE 1606 Activation of hepatic stellate cells Activation, hepatic stellate cells
KE 459 Increased, Liver Steatosis Increased, Liver Steatosis
AO 1549 Liver Injury Liver Injury

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help
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

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

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

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

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

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

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

References

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