Stressor: 151
Title
Stressor Overview
AOPs Including This Stressor
| AOP Name | Evidence |
|---|---|
| Antagonist binding to PPARα leading to body-weight loss | High |
Events Including This Stressor
| Event Name |
|---|
| Binding as antagonist, Antagonist binding to PPARalpha ligand binding domain |
| Binding of antagonist, PPAR alpha |
| stabilization, PPAR alpha co-repressor |
Chemical Table
AOP Evidence
Antagonist binding to PPARα leading to body-weight loss
GW6471 - Specifically designed molecules such as the PPARα antagonists GW6471 can bind to PPARα selectively recruiting binding of co-repressors to the PPARα nuclear signaling complex (Xu et al 2002).
Event Evidence
Binding as antagonist, Antagonist binding to PPARalpha ligand binding domain
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).
Binding of antagonist, PPAR alpha
Binding to PPAR alpha is implied given observations of inhibited PPAR alpha nuclear signaling inhibition by nitrotoluenes (Wilbanks et al 2014).
stabilization, PPAR alpha co-repressor
There is no evidence text for this event.
Stressor Info
Chemical/Category Description
GW6471 is a pharmaceutical developed for human diabetes research. GW6471 was designed specifically to inhibit PPAR alpha signaling (Xu et al 2002).
Characterization of Exposure
GW6471 was administered in biochemical and cell-free assays (Xu et al 2002).
References
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.