Tetradecylselenoacetic Acid, a PPAR Ligand With Antioxidant, Antiinflammatory, and Hypolipidemic Properties

Abstract

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. Methods and 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 ␤-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. A therosclerosis is regarded as an inflammatory disorder of the vascular wall, where multiple factors contribute to a persistent and self-perpetual inflammation within the atherosclerotic lesions. [1][2][3][4][5] There is also a consensus that atherosclerosis represents a state of elevated oxidative stress characterized by lipid and protein oxidation in the vascular wall. 6 Enhanced inflammation and oxidative stress seem to represent a vicious circle in atherogenesis, and therapeutic options directed against these processes seems like a reasonable approach in the management of atherosclerotic disorders.We have previously shown that tetradecylthioacetic acid (TTA), a modified fatty acid with a sulfur atom in the third position of the carbon backbone, promotes mitochondrial and peroxisomal proliferation, and decreases serum lipid levels in animal models. 7-9 TTA also shows antioxidant effects in vitro 10 and encompasses antiinflammatory properties in human leukocytes. 11 The pleiotropic effects of TTA seem to involve activation of peroxisome proliferator-activated receptors (PPARs), 12,13 which are receptors that serves as an important link between lipid metabolism and inflammation. 14 -17 Tetradecylselenoacetic acid (TSA) is a novel fatty acid which in comparison to TTA has a selenium atom instead of a sulfur atom in third position of the carbon backbone. As with TTA, 18 this modification makes TSA resistant to fatty acid ␤-oxidation. A previous in vitro study has demonstrated that TSA is a stronger antioxidant than TTA. 19 Based on these findings and its relation to TTA, we hypothesized that TSA also exerts poten...

Wedelolactone Regulates Lipid Metabolism and Improves Hepatic Steatosis Partly by AMPK Activation and Up-Regulation of Expression of PPARα/LPL and LDLR

“…These findings suggest that following wedelolactone treatment in HepG2 cells, LPL is a downstream target of PPARα, and that wedelolactone up-regulates LPL expression via PPARα up-regulation. Previous studies report that activation of PPARα typically induces the up-regulation of CPT1 and CD36 expression [ 15 , 16 ]. However, in HepG2 cells, CPT1 and CD36 remained unchanged after wedelolactone treatment in our study ( Fig 4 ).…”

Influence of epigenetic modifications of the interleukin‐10 promoter on IL10 gene expression

“…This finding is in line with results presented previously (21, 23), in which inhibition of histone deacetylation using TSA did not alter IL10 gene expression. Conversely, in studies on human blood leukocytes and bone‐derived macrophages, stimulation with LPS and treatment with TSA resulted in an increase in the production of IL‐10 (28, 29). The increase in expression of the IL10 gene after treatment of cells with butyrate, found in the present study, is in accordance with results presented previously (30).…”

Hypolipidemic Activity in Sprague–Dawley Rats and Constituents of a Novel Natural Vegetable Oil from Cornus Wilsoniana Fruits

“…The mRNA levels of PPAR target genes, acyl‐CoA oxidase (ACO) and carnitine palmitoyltransferase I (CPT1), in the rat liver were analyzed according to the reported method (Dyroy and others 2007). Total RNA was extracted from rat liver by the acid guanidium thiocyanate‐phenol‐chloroform method.…”