Comprehensive analysis of PPARγ 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 γ (PPARγ), a therapeutic target for diabetes, and analyzed PPARγ 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 PPARγ ligand-binding domain (LBD). Direct binding of HODE isomers to PPARγ LBD was determined by water-ligand observed via gradient spectroscopy (WaterLOGSY) NMR experiments. In contrast, there were differences in PPARγ 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 PPARγ-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 PPARγ agonist activity. These results indicate that all HODE isomers have PPARγ-binding affinity; however, they have different PPARγ agonist activity. Our findings may help to understand the biological function of lipid peroxidation products.

Comprehensive metabolomics profiling reveals common metabolic alterations underlying the four major non-communicable diseases in treated HIV infection

“…Interestingly, for HIV+ SCA, above elevations in lipid mediators or depressions in ether lipids were observed at ages 45–60 years only, whereas 9-HODE and 9(S)-HOTrE were elevated at ages18–29 years only. HODEs are stable oxidation products, usually increased when oxidative stress is increased [33] , and has been linked to atherosclerosis in the general population [34] . Thus, there is a possibility that HODEs may play a more important role in early onset of atherosclerosis.…”

No Effect of Dietary Fish Oil Supplementation on the Recruitment of Brown and Brite Adipocytes in Mice or Humans under Thermoneutral Conditions

“…[ 68 ] However, our own findings point towards a function for these two metabolites as negative regulators of thermogenic adipocytes in vivo, [ 69 ] possibly due to their function as ligands for peroxisome proliferator‐activated receptor γ, the master regulator of adipogenesis. [ 70 ] Thus, high WAT levels of 9‐HODE, 13 HODE and 18‐HEPE may at least partially explain the inability of n3‐PUFA supplemented diets to recruit brown and brite adipocytes in mice of our study.…”

Nuclear Hormone Receptors and Their Ligands: Metabolites in Control of Transcription

“…Rather, receptors recognize other derivatives of the four main classes of metabolites described above. For example, PPARγ binds to modified fatty acids, hydroxylated polyunsaturated fatty acids and prostaglandins [51][52][53], whereas FXR binds bile acids [32,33], which are modified terpenes.…”