Tetradecylselenoacetic acid, a PPAR ligand with antioxidant, antiinflammatory, and hypolipidemic properties.
OBJECTIVE
Antioxidants protect against oxidative stress and inflammation, which, in combination with hyperlipidemia, are important mediators of atherogenesis. Here we present a selenium-substituted fatty acid, tetradecylselenoacetic acid (TSA), which is hypothesized to have antioxidant, antiinflammatory, and hypolipidemic properties.


RESULTS
We show that TSA exerts antioxidant properties by delaying the onset of oxidation of human low density lipoprotein (LDL), by reducing the uptake of oxidized LDL in murine macrophages, and by increasing the mRNA level of superoxide dismutase in rat liver. TSA also showed antiinflammatory effects by suppressing the release of interleukin (IL)-2 and -4, and by increasing the release of IL-10 in human blood leukocytes. In addition, TSA decreased the plasma triacylglycerol level and increased the mitochondrial fatty acid beta-oxidation in rat liver. In pigs, TSA seemed to reduce coronary artery intimal thickening after percutaneous coronary intervention. In HepG2 cells TSA activated all peroxisome proliferator-activated receptors (PPARs) in a dose-dependent manner.


CONCLUSIONS
Our data suggest that TSA exert potent antioxidant, antiinflammatory, and hypolipidemic properties, potentially involving PPAR-related mechanisms. Based on these effects, it is tempting to hypothesize that TSA could be an interesting antiatherogenic approach to atherosclerotic disorders.
Dyrøy
Endre
E
Institute of Medicine, Section of Medical Biochemistry, University of Bergen, Norway.
Røst
Therese H
TH
Pettersen
Reidar J
RJ
Halvorsen
Bente
B
Gudbrandsen
Oddrun A
OA
Ueland
Thor
T
Muna
Ziad
Z
Müller
Fredrik
F
Nordrehaug
Jan E
JE
Aukrust
Pål
P
Berge
Rolf K
RK
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D050197:Atherosclerosis / Q000188:drug therapy*; D015152:Blotting, Northern; D002478:Cells, Cultured; D008078:Cholesterol, LDL / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D006949:Hyperlipidemias / Q000188:drug therapy*; D007962:Leukocytes / Q000187:drug effects; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D047492:Peroxisome Proliferator-Activated Receptors / Q000494:pharmacology*; D011336:Probability; D012313:RNA / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D012680:Sensitivity and Specificity; D013552:Swine
D000975:Antioxidants; D008078:Cholesterol, LDL; D047492:Peroxisome Proliferator-Activated Receptors; D012313:RNA