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Event: 2409

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Altered, Glucocorticoid receptor signaling

Short name

The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help

Altered, GR signaling

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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help

Level of Biological Organization
Molecular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Cell term
hepatocyte

Organ term

Organ term
liver

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Term	Scientific Term	Link
Homo sapiens	Homo sapiens	NCBI
Mus musculus	Mus musculus	NCBI
Rattus norvegicus	Rattus norvegicus	NCBI
mammals	mammals	NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Life stage	Evidence
Adults

Sex Applicability

An indication of the the relevant sex for this KE. More help

Term	Evidence
Unspecific

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

The glucocorticoid receptor (GR; NR3C1) is a ligand-activated nuclear receptor that regulates transcription of genes involved in glucose metabolism, lipid metabolism, inflammation, stress responses, and energy homeostasis. Upon binding endogenous glucocorticoids (e.g., cortisol, corticosterone) or exogenous ligands, GR translocates to the nucleus and modulates gene expression via glucocorticoid response elements or interaction with other transcription factors.

“Altered GR signaling” refers to a sustained increase or decrease in receptor activation, nuclear translocation, transcriptional activity, or downstream gene regulation relative to physiological homeostasis. Alterations may arise from:

Agonistic or antagonistic chemical interaction
Modulation of receptor expression levels
Changes in ligand availability
Disruption of receptor co-regulator recruitment
Post-translational modifications affecting GR function

In metabolic tissues such as liver and adipose tissue, altered GR signaling can disrupt insulin sensitivity, lipid handling, lipoprotein metabolism, de novo lipogenesis, mitochondrial function, and ER homeostasis. As such, perturbation of GR signaling represents a plausible molecular initiating event for adverse metabolic and hepatic outcomes.

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

GR signaling alterations can be measured at multiple levels:

1. Receptor Binding

Competitive ligand binding assays
Radioligand displacement assays

2. Transactivation/Transrepression Assays

Reporter gene assays (GRE-luciferase systems)
Nuclear receptor screening platforms

3. Nuclear Translocation

Immunofluorescence microscopy
Western blotting of cytoplasmic vs nuclear fractions

4. Gene Expression

Quantitative PCR of GR target genes (e.g., GILZ, PEPCK, G6Pase)
RNA sequencing

5. Protein Expression

Western blot or ELISA for GR-regulated metabolic enzymes

Validated in vitro assays for nuclear receptor activation provide moderate to high confidence in detecting GR perturbation. In vivo confirmation is typically based on transcriptional signatures and physiological endpoints (e.g., glucose intolerance).

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

This KE is applicable primarily to mammals, where GR signaling regulates systemic metabolic homeostasis. The receptor is highly conserved structurally and functionally across vertebrates; however, quantitative sensitivity may vary across taxa.

The strongest empirical evidence supporting this KE in the context of metabolic liver disease derives from:

Human clinical observations of glucocorticoid excess
Rodent models of chronic glucocorticoid exposure
In vitro hepatocyte and adipocyte systems

The weight of evidence for the biological plausibility of this KE is strong due to well-characterized receptor biology and extensive literature on GR-mediated metabolic regulation.

References

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