title: Long-chain metabolites of α-tocopherol occur in human serum and inhibit macrophage foam cell formation in vitro.
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.
authors.affiliation: Department of Nutritional Biochemistry, Institute of Nutrition, Friedrich Schiller University Jena, 07743 Jena, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Wallert
authors.affiliation: Department of Molecular Hemostaseology, University Hospital Jena, Jena, Germany.
authors.forename: Sandy
authors.initials: S
authors.lastname: Mosig
authors.affiliation: Department of Molecular Hemostaseology, University Hospital Jena, Jena, Germany.
authors.forename: Knut
authors.initials: K
authors.lastname: Rennert
authors.affiliation: Department of Molecular Hemostaseology, University Hospital Jena, Jena, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Funke
authors.affiliation: Department of Human Nutrition, Institute of Nutrition, Friedrich Schiller University Jena, 07743 Jena, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Ristow
authors.affiliation: Laboratory of Molecular Modeling and Chemoinformatics, Department of Chemistry, University of Perugia, Perugia, Italy.
authors.forename: Roberto Maria
authors.initials: RM
authors.lastname: Pellegrino
authors.affiliation: Laboratory of Molecular Modeling and Chemoinformatics, Department of Chemistry, University of Perugia, Perugia, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Cruciani
authors.affiliation: Section of Applied Biochemistry and Nutritional Sciences, Department of Internal Medicine, University of Perugia, Perugia, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Galli
authors.affiliation: Department of Nutritional Biochemistry, Institute of Nutrition, Friedrich Schiller University Jena, 07743 Jena, Germany. Electronic address: stefan.lorkowski@uni-jena.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Lorkowski
authors.affiliation: Department of Human Nutrition, Institute of Nutrition, Friedrich Schiller University Jena, 07743 Jena, Germany. Electronic address: marc.birringer@he.hs-fulda.de.
authors.forename: Marc
authors.initials: M
authors.lastname: Birringer
mesh_terms: D000975:Antioxidants / Q000378:metabolism*; D018955:CD36 Antigens / Q000378:metabolism; D002839:Chromans / Q000378:metabolism; D005487:Foam Cells / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D024502:alpha-Tocopherol / Q000097:blood*
chemical_list: D000975:Antioxidants; D018955:CD36 Antigens; D002839:Chromans; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; C099252:oxidized low density lipoprotein; C029141:2,2,5,7,8-pentamethyl-1-hydroxychroman; D024502:alpha-Tocopherol
keywords: Atherosclerosis; Free radicals; Macrophage foam cells; α-13′-COOH; α-13′-OH; α-Tocopherol