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Event: 1000

Key Event Title

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

stabilization, PPAR alpha co-repressor

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
stabilization, PPAR alpha co-repressor
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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
transcription corepressor activity nuclear receptor corepressor 2 increased
transcription corepressor activity nuclear receptor corepressor 1 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 KeyEvent Kurt A. Gust (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
Homo sapiens Homo sapiens High NCBI
yeast Saccharomyces cerevisiae Moderate NCBI

Life Stages

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

Sex Applicability

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

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 transcription co-repressors, silencing mediator for retinoid and thyroid hormone receptors (SMRT) and nuclear receptor co-repressor (N-CoR) have been observed to compete with transcriptional co-activators for binding to nuclear receptors (including PPARα) thus suppressing basal transcriptional activity (Nagy et al 1999, Xu et al 2002).  Binding motifs for the co-repressors and co-activators to PPARα have been observed to be conserved, however the co-repressor blocks the AF-2 helix from adopting the active conformation, as demonstrated in x-ray crystallography results presented in Xu et al (2002).  PPARα agonists and antagonists have been developed to selectively enhance co-activator or co-repressor binding, respectively (Xu et al 2001, Xu et al 2002).  Regarding the present key event, the prior binding of a PPARα antagonists such as GW6471 can stabilize the binding of the co-repressors to the PPARα signaling complex suppressing nuclear signaling and thus downstream transcription of PPARα-regulated genes.  Additionally, a natural human variant (V227A) in the hinge region of PPARα has been demonstrated to stabilize PPARα/N-CoR interactions resulting in inhibited transactivation of downstream genes in hepatic cells (Liu et al 2008) which can ultimately lead to measurable phenotypic effects of decreased blood triglycerides (Chan et al 2016).  The Liu et al (2008) study also demonstrated that the transactivation activity in the V227A variant could be restored when N-CoR was silenced.

Wilbanks et al. (2014) and Gust et al (2015) demonstrated inhibition of human PPARα nuclear signaling in in vitro nuclear signaling bioassays in response to 2,4-dinitrotoluene(2,4-DNT) and 2-amino-4,6-dinitrotoluene (2A-DNT), respectively.  However, it is unknown if this response was manifested through the co-repressor binding stabilization that was identified in Xu et al (2002).

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

Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible?

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).  Liu et al (2008) conducted in vitro investigations comparing human PPARα WT versus the V227A mutant in cell-based assays evaluated using quantitative real-time RT-PCR, competitive binding assays, immunofluorescence, glutathione-S-transferase (GST) pulldown, chromatin immunoprecipitation (ChIP).  In Chan et al (2006) triglycerides were measured directly from human blood serum samples from populations having the wild type PPARα gene compared to those having the V227A variant genotype.

The effects of 2,4-DNT and 2A-DNT on PPAR signaling was investigated using nuclear receptor reporter assays were conducted for (PPARalpha, PPARgamma, PPARsigma, and RXRalpha human cell-based assays, (Indigo Biosciences).

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 co-repressor antagonism of nuclear signaling by SMRT and N-CoR have been observed to be equivalent when comparing humans and yeast (Nagy et al 1999).  Therefore, the taxonomic applicability should be broad across eukaryotes.  However, the mechanistic perspective for SMRT, N-CoR and PPARα interactions described above was developed exclusively with the human PPARα system.  Also, the PPARα nuclear signaling in response to 2,4-DNT and 2A-DNT was established in a human in vitro system.

References

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

Chan, E., Tan, C.S., Deurenberg-Yap, M., Chia, K.S., Chew, S.K., Tai, E.S., 2006. The V227A polymorphism at the PPARα locus is associated with serum lipid concentrations and modulates the association between dietary polyunsaturated fatty acid intake and serum high density lipoprotein concentrations in Chinese women. Atherosclerosis 187, 309-315.

Gust KA, Nanduri B, Rawat A, Wilbanks MS, Ang CY, Johnson DR, Pendarvis K, Chen X, Quinn Jr. MJ, Johnson MS, Burgess SC, Perkins EJ. 2015. Systems Toxicology Identifies Mechanistic Impacts of 2-amino-4,6-dinitrotoluene (2A-DNT) Exposure in Northern Bobwhite. BMC Genomics. 16:587  doi:10.1186/s12864-015-1798-4.

Liu, M.H., Li, J., Shen, P., Husna, B., Tai, E.S., Yong, E.L., 2008. A natural polymorphism in peroxisome proliferator-activated receptor-alpha hinge region attenuates transcription due to defective release of nuclear receptor corepressor from chromatin. Mol. Endocrinol. 22, 1078-1092.

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.

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.

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.

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.