Upstream eventBinding of antagonist, PPAR alpha
stabilization, PPAR alpha co-repressor
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Antagonist binding to PPARα leading to body-weight loss||non-adjacent||High||Moderate|
Life Stage Applicability
|Not Otherwise Specified||Not Specified|
Key Event Relationship Description
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). 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 nuclear signaling activity (Nagy et al 1999, Xu et al 2002). Regarding the present MIE, PPARα antagonists such as GW6471 which leads to the KE where increased binding and stabilization of the co-repressors to the PPARα signaling complex suppressing nuclear signaling.
Evidence Supporting this KER
As a demonstration of the connection between this MIE and the KE, it has been demonstrated that antagonists such as GW6471 bound to PPARα can recruit and stabilize the binding of co-repressors to the PPARα signaling complex suppressing nuclear signaling (Xu et al. 2002). This relationship has been demonstrated using x-ray crystallography and a variety of additional binding and signaling assays (Xu et al 2002). 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). Therefore, this KER received the score of “strong”.
The biological plausibility is high given the crystal structure resolved for the bound group of GW6471, the co-repressor SMRT, and PPARα where the ligand binding domain of PPARα was set in the inactive conformation (Xu et al 2002).
Include consideration of temporal concordance here
The inclusion of GW6471 was observed to recruit binding of the co-repressors SMRT and NCOR to PPARα in a positive dose-responsive manner (Xu et al 2002). Additionally, the application of the antagonist GW6471 was observed to displace the PPARα agonist GW409544 thus reducing PPARα signaling (Xu et al 2002) .The MIE occurs in advance of co-repressor recruitment and changes in PPARα signaling (Xu et al 2002).
Uncertainties and Inconsistencies
Regarding the present MIE, GW6471 has highly specific binding to the SMRT and N-CoR binding domains (Nagy et al 1999, Xu et al 2002). The degree to which other chemicals cause PPARα antagonism by this specific MIE needs to be explored. For example, 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).
Quantitative Understanding of the Linkage
Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships?
A concentration-response curve has been developed for GW6471 recruiting binding of the SMRT and N-CoR co-repressors to the PPARα complex (Xu et al 2002).
Rapid Molecular Interactions.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
The majority of the studies cited herein provide evidence for human and rat, however much of the signaling architecture is also present in yeast (Krogsdam et al 2002).
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. In Press.
Krogsdam AM, Nielsen CA, Neve S, Holst D, Helledie T, Thomsen B, et al. 2002. Nuclear receptor corepressor-dependent repression of peroxisome-proliferator-activated receptor delta-mediated transactivation. Biochem J 363:157-165.
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, et al. 2001. Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors. Proceedings of the National Academy of Sciences 98:13919-13924.
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.