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.
Rode
Sabine
S
Institute for Prophylaxis of Cardiovascular Diseases, University of Munich, Pettenkoferstr. 9, 80637 Munich, Germany.
Rubic
Tina
T
Lorenz
Reinhard L
RL
D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors*; D000975:Antioxidants / Q000494:pharmacology*; D050197:Atherosclerosis / Q000209:etiology / Q000517:prevention & control; D018955:CD36 Antigens / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005487:Foam Cells / Q000187:drug effects* / Q000378:metabolism; D017930:Genes, Reporter / Q000187:drug effects; D006801:Humans; D008077:Lipoproteins, LDL / Q000494:pharmacology; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D024502:alpha-Tocopherol / Q000494:pharmacology*
C577836:ABCA1 protein, human; C419353:ABCG1 protein, human; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D000975:Antioxidants; D018955:CD36 Antigens; D008076:Cholesterol, HDL; D004268:DNA-Binding Proteins; D008077:Lipoproteins, LDL; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; C099252:oxidized low density lipoprotein; D002784:Cholesterol; D024502:alpha-Tocopherol