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

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Gorczynski MJ, Smitherman PK, Akiyama TE, Wood HB, Berger JP, King SB, Morrow CS

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

J Med Chem. 2009 Aug 13;52(15):4631-9. doi: 10.1021/jm900326c.

PubMed ID

19719236 [ View in PubMed

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Abstract

Nitroalkene fatty acids are potent endogenous ligand activators of PPARgamma-dependent transcription. Previous studies with the naturally occurring regioisomers of nitrolinoleic acid revealed that the isomers are not equivalent with respect to PPARgamma activation. To gain further insight into the structure-activity relationships between nitroalkenes and PPARgamma, 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 PPARgamma activation. Interestingly, at higher concentrations (>2 microM) 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 PPARgamma 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).

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Rosiglitazone	Peroxisome proliferator-activated receptor alpha	IC 50 (nM)	>15000	N/A	N/A	Details
Rosiglitazone	Peroxisome proliferator-activated receptor gamma	IC 50 (nM)	250	N/A	N/A	Details