Two homoisoflavonoids act as peroxisome proliferator-activated receptor agonists

Abstract

Polygonatum odoratum (Mill.) Druce is a well-known traditional Chinese medicine exerting multi-biological functions like removing dryness, promoting secretion of fluid, and quenching thirst, but its molecular mechanism is not fully understood. Peroxisome proliferator-activated receptor (PPAR) γ is a member of nuclear receptor superfamily, and its agonists are prescribed as anti-hyperglycemic drugs. In this study, homoisoflavonoids isolated from P. odoratum were evaluated for their activity against PPARγ by the fluorescence polarization competitive binding assay and transient transfection reporter assays. Primarily, the fluorescence polarization competitive binding assay results showed that 5,7-dihydroxy-6, 8-dimethyl-3-(4′-hydroxybenzyl)chroman-4-one (IC50 = 7 μM) and 5,7-dihydroxy-6-methyl-8-methoxy-3-(4′-hydroxybenzyl)chroman-4-one (IC50 = 12 μM) bound to PPARγ ligand-binding domain with fair binding affinity. Moreover, both homoisoflavonoids transactivated PPARγ-dependent promoters including PPRE (PPARγ response element), SHP, and ABCA1 gene promoters in dose-dependent manner. Further molecular modeling studies demonstrated that they interacted with PPARγ ligand-binding pocket in a similar manner as indeglitazar, a novel PPARγ agonist. All these results highly indicated that 5,7-dihydroxy-6, 8-dimethyl-3-(4′-hydroxybenzyl)chroman-4-one and 5,7-dihydroxy-6-methyl-8-methoxy-3-(4′-hydroxybenzyl)chroman-4-one are the active constituents of P. odoratum and act as PPARγ agonists.