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

Abstract

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.

• Authors: Sabine Rode, Tina Rubic, Reinhard L Lorenz
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 369 Issue 3 Pg. 868-72 (May 09 2008) ISSN: 1090-2104 [Electronic] United States
• PMID: 18328805 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ABCA1 protein, human
• ABCG1 protein, human
• ATP Binding Cassette Transporter 1
• ATP Binding Cassette Transporter, Subfamily G, Member 1
• ATP-Binding Cassette Transporters
• Antioxidants
• CD36 Antigens
• Cholesterol, HDL
• DNA-Binding Proteins
• Lipoproteins, LDL
• Liver X Receptors
• NR1H3 protein, human
• Orphan Nuclear Receptors
• Receptors, Cytoplasmic and Nuclear
• oxidized low density lipoprotein
• Cholesterol
• alpha-Tocopherol

Topics

• ATP Binding Cassette Transporter 1
• ATP Binding Cassette Transporter, Subfamily G, Member 1
• ATP-Binding Cassette Transporters (antagonists & inhibitors)
• Antioxidants (pharmacology)
• Atherosclerosis (etiology, prevention & control)
• CD36 Antigens (metabolism)
• Cholesterol (metabolism)
• Cholesterol, HDL (pharmacology)
• DNA-Binding Proteins (agonists, antagonists & inhibitors, metabolism)
• Foam Cells (drug effects, metabolism)
• Genes, Reporter (drug effects)
• Humans
• Lipoproteins, LDL (pharmacology)
• Liver X Receptors
• Orphan Nuclear Receptors
• Receptors, Cytoplasmic and Nuclear (agonists, antagonists & inhibitors, metabolism)
• Transcription, Genetic (drug effects)
• alpha-Tocopherol (pharmacology)