stabilization, PPAR alpha co-repressor leads to Decreased, PPARalpha transactivation of gene expression

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). 

Unknown.

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.

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.