α-Tocopherol disturbs macrophage LXRα regulation of ABCA1/G1 and cholesterol handling

Based on the oxidation hypothesis high doses of α-tocopherol have been advocated to prevent atherosclerosis, but clinical trials failed to demonstrate a benefit. As specific oxylipids activate PPARγ and LXRα, master regulators of lipid metabolism and cholesterol exporters, we hypothesized, that high dose α-tocopherol might interfere with reverse cholesterol transport out of the vessel wall. Human THP-1 cells, a foam cell model, were preincubated with α-tocopherol or carrier before exposure to oxidized LDL, delipidated HDL or control buffer. Specific mRNAs were quantified by real-time RT-PCR, LXRα activation by a reporter gene assay and cellular cholesterol homeostasis by oxLDL and dHDL facilitated uptake and efflux assays. α-Tocopherol significantly reduced baseline expression and stimulation by oxLDL of LXRα activity, CD36, ABCA1, and ABCG1. α-Tocopherol also reversed the suppression of CD36 and ABCA1 by dHDL. Thus α-Tocopherol compromises cellular lipid scavenging and channelling of cholesterol into reverse transport out of the vessel wall.