alpha-Tocopherol disturbs macrophage LXRalpha regulation of ABCA1/G1 and cholesterol handling

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