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Event: 998

Key Event Title

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

Binding of antagonist, PPAR alpha

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
Binding of antagonist, PPAR alpha
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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
eukaryotic cell

Organ 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

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
Process Object Action
receptor antagonist activity peroxisome proliferator-activated receptor alpha increased

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
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
PPARα antagonism leading to body-weight loss MolecularInitiatingEvent Agnes Aggy (send email) Open for citation & comment WPHA/WNT Endorsed

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 Evidence Link
human Homo sapiens High NCBI
Saccharomyces cerevisiae Saccharomyces cerevisiae High NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help
Life stage Evidence
Not Otherwise Specified

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

Binding of molecules to peroxisome proliferator-activated receptor α (PPARα) can cause either agonistic or antagonistic signaling depending on molecular structure (Xu et al 2001, Xu et al 2002). Certain molecules that can bind to the PPARα ligand binding domain have been observed to cause conformational changes that induce increased affinity to co-repressors which decrease PPARα nuclear signaling (Xu et al 2002). Binding of co-repressors such as the silencing mediator for retinoid and thyroid hormone receptors (SMRT) and nuclear receptor co-repressor (N-CoR) to PPARα is reinforced by the antagonist, which blocks the AF-2 helix from adopting the active conformation, as demonstrated in x-ray crystallography results presented in Xu et al (2002). Thus, molecules that bind to PPARα that can enhance co-repressor binding act as PPARα antagonists.

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

In Xu et al (2002), X-ray crystallography was used to characterize the suppressed PPARα signaling complex (PPARα / GW6471 / SMRT) and was compared against the activated PPARα complex which included binding of PPARα with the agonist GW409544 and the co-activator, steroid receptor coactivator-1 (SRC-1). For simple PPARα binding assessment, competitive binding assays are availables, however these must be coupled with nuclear signaling activation / inhibition assays to determine if chemicals are agonists or antagonists.

Domain of Applicability

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

The fundamental mechanics for nuclear receptor binding as well as demonstration of co-repressor recruitment have been observed to be conserved when comparing humans and yeast (Nagy et al 1999). PPARα has been cloned from frogs, rats, guinea pigs, and humans where the DNA-binding domain has been shown to be identical across species, however the ligand binding domain has exhibited lower homology, likely adapted to differences in dietary ligands among species (Willson et al 2000). Overall, there is evidence for fairly conserved taxonomic applicability across vertebrates, though care should be given when extrapolating across species.

References

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

Nagy L, Kao H-Y, Love JD, Li C, Banayo E, Gooch JT, Krishna V, Chatterjee K, Evans RM, Schwabe JWR: Mechanism of corepressor binding and release from nuclear hormone receptors. Genes Dev 1999, 13(24):3209-3216.

Xu HE, Lambert MH, Montana VG, Plunket KD, Moore LB, Collins JL, Oplinger JA, Kliewer SA, Gampe RT, McKee DD et al: Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors. Proceedings of the National Academy of Sciences 2001, 98(24):13919-13924.

Wilbanks, M., Gust, K.A., Atwa, S., Sunesara, I., Johnson, D., Ang, C.Y., Meyer., S.A., and Perkins, E.J. 2014. Validation of a genomics-based hypothetical adverse outcome pathway: 2,4-dinitrotoluene perturbs PPAR signaling thus impairing energy metabolism and exercise endurance. Toxicological Sciences. 141(1):44-58.

Willson TM, Brown PJ, Sternbach DD, Henke BR: The PPARs:  From Orphan Receptors to Drug Discovery. J Med Chem 2000, 43(4):527-550.

Xu HE, Stanley TB, Montana VG, Lambert MH, Shearer BG, Cobb JE, McKee DD, Galardi CM, Plunket KD, Nolte RT et al: Structural basis for antagonist-mediated recruitment of nuclear co-repressors by PPAR[alpha]. Nature 2002, 415(6873):813-817.