Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 68, Issue -, Pages 43-51Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2013.11.009
Keywords
alpha-Tocopherol; alpha-13 '-OH; alpha-13 '-COOH; Atherosclerosis; Macrophage foam cells; Free radicals
Funding
- ErnestSolvay-Stiftung
- Thuringer Ministerium fur Bildung, Wissenschaft und Kultur
- Stiftung fur Technologie und Forschung Thuringen
- Forschungskreis der Ernahrungsindustrie
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Despite intensive research the physiological role and molecular mechanisms of action of the lipophilic antioxidant a-tocopherol (alpha-TOH) are still poorly understood. Hepatic alpha-TOH catabolism, results in intermediate formation of the long-chain metabolites (alpha-LCMs) alpha-13'-hydroxy- and alpha-13'-carboxychromanol (alpha-13'-OH and a-13'-COOH). We propose that alpha-LCMs have biological functions that need further exploration. Here we report that alpha-13'-COOH, as detected by LC/MS Q-TOF, occurs in human serum, providing evidence for its systemic bioavailability. Using semisynthetically derived, alpha-LCMs we performed flow cytometric analyses and found that alpha-LCMs decrease oxidized LDL (oxLDL) uptake (alpha-13'-OH, 24 +/- 6%, alpha-13'-COOH, 20 +/- 5% vs control) and oxLDL-induced lipid accumulation in human macrophages in vitro (alpha-13'-OH, 26 +/- 4%, alpha-13'-COOH, 21 +/- 9% vs oxLDL), probably owing to alpha-LCMmediated reduction in phagocytosis of oxLDL (alpha-13'-OH, 16 +/- 6%, alpha-13'-COOH, 41 +/- 3% vs oxLDL). At the same time, alpha-LCMs induced expression of CD36, the major scavenger receptor for oxLDL, in human macrophages by about 4.5-fold. Blocking experiments provided evidence that alpha-LCMs influence oxLDL uptake independent of CD36. A key finding of our study is that bioactivity of the alpha-LCMs occurs at lower concentrations and with mechanisms distinct from those of their metabolic precursor alpha-TOH. Our findings shed neW light on the mechanistic aspects of alpha-TOH function in macrophages, which seem to be complicated by circulating alpha-LCMs. We speculate that alpha-LCMs represent a new class of regulatory metabolites. Further studies are required to elucidate their physiological role and contribution to cardiovascular disease. (C) 2013 Elsevier Inc. All rights reserved.
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