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Free Radic Biol Med. 2014 Mar;68:43-51. doi: 10.1016/j.freeradbiomed.2013.11.009. Epub 2013 Dec 1.

Long-chain metabolites of α-tocopherol occur in human serum and inhibit macrophage foam cell formation in vitro.

Author information

1
Department of Nutritional Biochemistry, Institute of Nutrition, Friedrich Schiller University Jena, 07743 Jena, Germany.
2
Department of Molecular Hemostaseology, University Hospital Jena, Jena, Germany.
3
Department of Human Nutrition, Institute of Nutrition, Friedrich Schiller University Jena, 07743 Jena, Germany.
4
Laboratory of Molecular Modeling and Chemoinformatics, Department of Chemistry, University of Perugia, Perugia, Italy.
5
Section of Applied Biochemistry and Nutritional Sciences, Department of Internal Medicine, University of Perugia, Perugia, Italy.
6
Department of Nutritional Biochemistry, Institute of Nutrition, Friedrich Schiller University Jena, 07743 Jena, Germany. Electronic address: stefan.lorkowski@uni-jena.de.
7
Department of Human Nutrition, Institute of Nutrition, Friedrich Schiller University Jena, 07743 Jena, Germany. Electronic address: marc.birringer@he.hs-fulda.de.

Abstract

Despite intensive research the physiological role and molecular mechanisms of action of the lipophilic antioxidant α-tocopherol (α-TOH) are still poorly understood. Hepatic α-TOH catabolism results in intermediate formation of the long-chain metabolites (α-LCMs) α-13'-hydroxy- and α-13'-carboxychromanol (α-13'-OH and α-13'-COOH). We propose that α-LCMs have biological functions that need further exploration. Here we report that α-13'-COOH, as detected by LC/MS Q-TOF, occurs in human serum, providing evidence for its systemic bioavailability. Using semisynthetically derived α-LCMs we performed flow cytometric analyses and found that α-LCMs decrease oxidized LDL (oxLDL) uptake (α-13'-OH, 24±6%, α-13'-COOH, 20±5% vs control) and oxLDL-induced lipid accumulation in human macrophages in vitro (α-13'-OH, 26±4%, α-13'-COOH, 21±9% vs oxLDL), probably owing to α-LCM-mediated reduction in phagocytosis of oxLDL (α-13'-OH, 16±6%, α-13'-COOH, 41±3% vs oxLDL). At the same time, α-LCMs induced expression of CD36, the major scavenger receptor for oxLDL, in human macrophages by about 4.5-fold. Blocking experiments provided evidence that α-LCMs influence oxLDL uptake independent of CD36. A key finding of our study is that bioactivity of the α-LCMs occurs at lower concentrations and with mechanisms distinct from those of their metabolic precursor α-TOH. Our findings shed new light on the mechanistic aspects of α-TOH function in macrophages, which seem to be complicated by circulating α-LCMs. We speculate that α-LCMs represent a new class of regulatory metabolites. Further studies are required to elucidate their physiological role and contribution to cardiovascular disease.

KEYWORDS:

Atherosclerosis; Free radicals; Macrophage foam cells; α-13′-COOH; α-13′-OH; α-Tocopherol

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