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

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.