Sesquiterpene lactones from Tithonia diversifolia act as peroxisome proliferator-activated receptor agonists

Tithonia diversifolia is a well-known traditional Chinese medicine treating diabetes, hepatitis, and hepatocarcinoma but its molecular mechanism is not fully understood. Peroxisome proliferator-activated receptors (PPARs) alpha and gamma are members of nuclear receptor superfamily. Their agonists are prescribed as antihyperlipidemic and antihyperglycemic drugs now. In this study, sesquiterpene lactones, tirotundin and tagitinin A, were isolated from T. diversifolia and evaluated for their activity against PPARs by the transient transfection reporter assay. Tirotundin and tagitinin A transactivated PPAR gamma dependent promoters including PPRE (PPAR gamma response element), SHP, and ABCA1 gene promoters in dose-dependent manner. Furthermore, the fluorescence polarization competitive binding assay showed that tirotundin (IC50 = 27 mu M) and tagitinin A (IC50 = 55 mu M) enhanced PPAR gamma transactivation activity by directly binding to PPAR gamma ligand binding domain. Additionally, they stimulated the transactivation of PPAR alpha dependent SULT2A1 gene promoter by 2.3-fold of vehicle effect at 10 mu M. These results highly indicated that tirotundin and tagitinin A are the active components of T. diversifolia to exert anti-diabetic effect through PPAR gamma pathway. Moreover, these sesquiterpene lactones behaved as PPAR alpha/gamma dual agonists so they might be useful as the potential herbal treatment for diabetes. (C) 2012 Elsevier Ltd. All rights reserved.