Comprehensive analysis of PPAR? agonist activities of stereo-, regio-, and enantio-isomers of hydroxyoctadecadienoic acids.

ABSTRACT: Hydroxyoctadecadienoic acids (HODEs) are produced by oxidation and reduction of linoleates. There are several regio- and stereo-isomers of HODE, and their concentrations in vivo are higher than those of other lipids. Although conformational isomers may have different biological activities, comparative analysis of intracellular function of HODE isomers has not yet been performed. We evaluated the transcriptional activity of peroxisome proliferator-activated receptor ? (PPAR?), a therapeutic target for diabetes, and analyzed PPAR? agonist activity of HODE isomers. The lowest scores for docking poses of 12 types of HODE isomers (9-, 10-, 12-, and 13-HODEs) were almost similar in docking simulation of HODEs into PPAR? ligand-binding domain (LBD). Direct binding of HODE isomers to PPAR? LBD was determined by water-ligand observed via gradient spectroscopy (WaterLOGSY) NMR experiments. In contrast, there were differences in PPAR? agonist activities among 9- and 13-HODE stereo-isomers and 12- and 13-HODE enantio-isomers in a dual-luciferase reporter assay. Interestingly, the activity of 9-HODEs was less than that of other regio-isomers, and 9-(E,E)-HODE tended to decrease PPAR?-target gene expression during the maturation of 3T3-L1 cells. In addition, 10- and 12-(Z,E)-HODEs, which we previously proposed as biomarkers for early-stage diabetes, exerted PPAR? agonist activity. These results indicate that all HODE isomers have PPAR?-binding affinity; however, they have different PPAR? agonist activity. Our findings may help to understand the biological function of lipid peroxidation products.

SUBMITTER: Umeno A 

PROVIDER: S-EPMC7198041 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature