Mechanism of Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) Transactivation by Hesperetin Glucuronides Is Distinct from That by a Thiazolidine-2,4-dione Agent

Abstract

Hesperidin, a flavanone glycoside present abundantly in citrus fruits, is predominantly metabolized to hesperetin-7-O-β-D-glucuronide (H7-OG) and hesperetin-3′-O-β-D-glucuronide (H3′-OG), which exhibit partial agonistic activity towards peroxisome proliferator-activated receptor gamma (PPARγ). Here, in order to understand the mechanism(s) of action of PPARγ transactivation elicited by hesperetin glucuronides, we compared the transactivation activities of PPARγ (ligand-binding domain (LBD)) mutants by hesperetin glucuronides and troglitazone, a thiazolidine-2,4-dione class PPARγ full agonist. The assay results indicated that the mechanisms of activation of PPARγ by hesperetin glucuronides and by troglitazone are distinct, probably due to a difference in the binding sites of these compounds on the PPARγ LBD. Flavanone-class PPARγ partial agonists, luteolin and hesperetin glucuronides, showed similar activation profiles of the PPARγ LBD mutants, even though they have different side chain functionalities.