Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) by nitroalkene fatty acids: importance of nitration position and degree of unsaturation.

Nitroalkene fatty acids are potent endogenous ligand activators of PPAR gamma-dependent transcription. Previous studies with the naturally occurring regioisomers of nitrolinoleic acid revealed that the isomers are not equivalent with respect to PPAR gamma activation. To gain further insight into the structure-activity relationships between nitroalkenes and PPAR gamma, we examined additional naturally occurring nitroalkenes derived from oleic acid, 9-nitrooleic acid (E-9-NO2-18:1 [1]) and 10-nitrooleic acid (E-10-NO2-18:1 [2]), and several synthetic nitrated enoic fatty acids of variable carbon chain length, double bonds, and nitration site. At submicromolar concentrations, E-12-NO2 derivatives were considerably more potent than isomers nitrated at carbons 5, 6, 9, 10, and 13, and chain length (16 versus 18) or number of double bonds (1 versus 2) was of little consequence for PPAR gamma activation. Interestingly, at higher concentrations (> 2 mu M) the nitrated enoic fatty acids (E-9-NO2-18:1 [1], E-9-NO2-16:1 [3], E-10-NO2-18:1 [2], and E-12-NO2-18:1 [7]) deviated significantly from the saturable pattern of PPAR gamma activation observed for nitrated 1,4-dienoic fatty acids (E-9-NO2-18:2, E-10-NO2-18:2, E-12-NO2-18:2, and E-13-NO2-18:2).