Oxidized fatty acids from Clematis species activate peroxisome proliferator activated receptors (PPARs) in vitro

PPARs are ligand-activated transcription factors that belong to the nuclear receptor superfamily. They mainly regulate the expression of genes relevant for the metabolism of lipids and glucose. To date three PPAR isotypes are known (PPARα, PPARβ/δ and PPARγ), each of them possessing a distinct tissue distribution pattern and carrying out unique functions in the regulation of energy metabolism [1]. The stems of Clematis armandii Franch. (Ranunculaceae) (Chuanmutong) are used in traditional Chinese medicine for relieving rheumatism, clearing heat, promoting diuresis, and enhancing antibacterial host defense [2]. The aerial parts and roots of C. vitalba L. are traditionally used in Europe to treat inflammatory disorders. Based on this knowledge, C. armandii stem extracts of different polarity were tested in a PPAR-driven luciferase reporter gene assay in transiently transfected HEK-293 cells [3]. Activity-guided fractionation of the active ethyl acetate extract led to the isolation of the two oxidized fatty acids (10E,12Z)- 9-Hydroxy-10,12-octadecadienoic acid (9-HODE) and (10E,12E)- 9-Oxo-10,12-octadecadienoic acid (9-Oxo-ODE) (fig.1). Both compounds significantly activated all three PPAR isotypes, 9-oxo-ODE showing the stronger activity. Interestingly, oxidized fatty acids have been found to act as endogenous PPARα- and γ- ligands [4]. Unlike unsaturated hydroxy fatty acids such as 9-HODE, oxo fatty acids have been found to covalently bind to the PPARγ ligand binding domain through a Michael addition reaction due to their α,β unsaturated ketone moiety [4]. This also explains the higher activity observed for 9-Oxo-ODE. PPAR-β/δ agonistic activity of the two compounds has not been described so far.

In addition, 9-HODE and 9-oxo-ODE could also be identified in the aerial parts of C. vitalba.

Fig. 1: Structure of the PPAR-active constituents.

Acknowledgements: This study was supported by the FWF (NFN-project “Drugs from Nature Targeting Inflammation”, project Nr. S10704, S10705 and S10711).

Keywords: Clematis armandii, Clematis vitalba, PPAR, activity-guided fractionation

References:

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