Upstream eventstabilization, PPAR alpha co-repressor
Decreased, PPARalpha transactivation of gene expression
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Antagonist binding to PPARα leading to body-weight loss||adjacent||High||Moderate|
|Homo sapiens||Homo sapiens||High||NCBI|
Life Stage Applicability
|Not Otherwise Specified||Not Specified|
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). Natural human variant (V227A) in the hinge region of PPARα has also been demonstrated to stabilize PPARα/N-CoR interactions resulting in inhibited transactivation of downstream genes in hepatic cells, a response that was reversed when N-CoR was silenced. (Liu et al 2008). 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
Stabilization of co-repressors to the PPARα signaling complex suppresses nuclear signaling (Xu et al. 2002). Impaired PPARα nuclear signaling has been broadly demonstrated to decrease the transcriptional expression of PPARα-regulated genes (Kersten et al 2014). Thus, the KER for the KE “PPAR alpha co-repressor stabilization, increased” -> the KE “PPARalpha transactivation of gene expression, decreased” 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). Additionally, Krogsdam et al (2002) have established dose-response relationships for increasing N-CoR activity with decreased fold induction of PPARα transactivation potential.
Include consideration of temporal concordance here
See supporting evidence in previous bullets. The binding of the co-repressor to the PPARα complex occurs in advance of suppression of PPARα transactivation (Xu et al 2002).
Uncertainties and Inconsistencies
Given the observations that co-repressors can inhibit PPARα nuclear signaling (Xu et al 2002) and downstream transactivation potential (Krogsdam et al 2002), each in a dose-responsive manner, this provides strong evidence for the present KER. It should be noted however that 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.
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?
Krogsdam et al (2002) have established dose-response relationships for increasing N-CoR activity with decreased fold induction of PPARα transactivation potential.
Rapid Molecular Interactions.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
I'm in hell.
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). However, the mechanistic perspective for SMRT, N-CoR and PPARα interactions described above was developed exclusively with the human PPARα system.
Desvergne B, Wahli W (1999) Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocrine Reviews 20(5): 649-688.
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.
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.
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.