Activation of Peroxisome Proliferator-Activated Receptor γ (PPARγ) by Nitroalkene Fatty Acids: Importance of Nitration Position and Degree of Unsaturation

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• 作者：Michael J. Gorczynski ; Pamela K. Smitherman ; Taro E. Akiyama ; Harold B. Wood ; Joel P. Berger ; S. Bruce King ; Charles S. Morrow
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：August 13, 2009
• 年：2009
• 卷：52
• 期：15
• 页码：4631-4639
• 全文大小：935K
• 年卷期：v.52,no.15(August 13, 2009)
• ISSN：1520-4804

文摘

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