Upstream eventBinding as antagonist, Antagonist binding to PPARalpha ligand binding domain
Decreased, PPARalpha transactivation of gene expression
Key Event Relationship Overview
AOPs Referencing Relationship
|Homo sapiens||Homo sapiens||High||NCBI|
|Rattus rattus||Rattus rattus||High||NCBI|
Life Stage Applicability
Key Event Relationship Description
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). Regarding the present MIE, PPARα antagonists such as GW6471 stabilize the binding of co-repressors to the PPARα signaling complex suppressing nuclear signaling and thus downstream transactivation-transcription of PPARα-regulated genes. Given that PPARα trans-activation induces catabolism of fatty acids, this signaling pathway has been broadly demonstrated to play a key role in energy homeostasis (Kersten 2014, Evans et al 2004, Desvergne and Wahli 1999).
Evidence Supporting this KER
Specific Weight of Evidence scoring for all KEs and KERs in this AOP are provided in Collier et al (2016). PPARα antagonists such as GW6471 stabilize the binding of co-repressors to the PPARα signaling complex suppressing nuclear signaling (Xu et al. 2002) and thus downstream transcription of PPARα-regulated genes which is supported by a vast array of studies (see https://aopkb.org/aopwiki/index.php/Aop:6 for literature review), thus the KER for the MIE KE1 received the score of “strong”.
The biological plausibility is high given the lock-and-key mechanism identified for the binding of GW6471 to the co-repressor of PPARα signaling complex which inhibits PPARα transactivation (Xu et al 2002).
Include consideration of temporal concordance here
See supporting evidence in previous bullets. The MIE occurs in advance of suppression of PPARα transactivation (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 binding to the SMRT and N-CoR co-repressors of the PPARα complex (Xu et al 2002). Krogsdam et al (2002) have established dose-response relationships for increasing N-CoR activity with decreased fold induction of PPARα transactivation potential. There are a variety of structural elements included in the PPARα nuclear signaling complex, including the action of co-activators (Xu et al 2001), so there is potential for modifiers in the signaling cascade.
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).
Desvergne B, Wahli W (1999) Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocrine Reviews 20(5): 649-688.
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.
Evans RM, Barish GD, Wang YX: PPARs and the complex journey to obesity. Nat Med 2004, 10(4):355-3
Kersten S. 2014. Integrated physiology and systems biology of PPARalpha. Molecular Metabolism 2014, 3(4):354-371.
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.