Targeting the Alternative Vitamin E Metabolite Binding Site Enables Noncanonical PPAR Modulation

The lipid-sensingtranscription factor PPAR & gamma; isthe targetof antidiabetic thiazolidinediones (TZD). At two sites within itsligand binding domain, it also binds oxidized vitamin E metabolitesand the vitamin E mimetic garcinoic acid. While the canonical interactionwithin the TZD binding site mediates classical PPAR & gamma; activation,the effects of the second binding on PPAR & gamma; activity remain elusive.Here, we identified an agonist mimicking dual binding of vitamin Emetabolites and developed a selective ligand of the second site, unveilingpotential noncanonical regulation of PPAR & gamma; activities. We foundthat this alternative binding event can simultaneously occur withorthosteric ligands and it exerted different effects on PPAR & gamma;-cofactorinteractions compared to both orthosteric PPAR & gamma; agonists andantagonists, indicating the diverse roles of the two binding sites.Alternative site binding lacked the pro-adipogenic effect of TZD andmediated no classical PPAR signaling in differential gene expressionanalysis but markedly diminished FOXO signaling, suggesting potentialtherapeutic applications.