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 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).
Gorczynski
Michael J
MJ
Department of Chemistry, Wake Forest University, Winston-Salem, North Carolina 27157, USA.
Smitherman
Pamela K
PK
Akiyama
Taro E
TE
Wood
Harold B
HB
Berger
Joel P
JP
King
S Bruce
SB
Morrow
Charles S
CS
D000475:Alkenes / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D005227:Fatty Acids / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D047495:PPAR gamma / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
D000475:Alkenes; D005227:Fatty Acids; D047495:PPAR gamma