Premium
Modulation of cholesterol transport by oxidative stress in THP‐1 macrophages
Author(s) -
Marcil Valérie,
André Trembaly,
JeanClaude Lavoie,
Emile Levy
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a137-d
Subject(s) - abca1 , oxidative stress , lipid peroxidation , chemistry , liver x receptor , cholesterol , scavenger receptor , foam cell , efflux , transporter , biochemistry , nuclear receptor , lipoprotein , transcription factor , gene
Foam cell formation constitutes a crucial step in atherosclerosis development. Several cholesterol transporters and signalling pathways are involved in this process. It has also been shown that oxidative stress is highly implicated in atherogenic events. The aims of this study are to determine the effect of oxidative stress on cholesterol flux and on its transporters ABCA1 and SR‐B1, as well as to identify the mechanisms involved in their regulation. To this end, we treated THP‐1 macrophages with iron/ascorbate (100/1000μM) for a period of 2 and 4 hours in order to assess oxidative stress. To neutralize lipid peroxidation, we used the antioxidants Trolox (0.5mM) and BHT (0.5mM). Iron/ascorbate led to strong peroxidation as shown by the elevation of MDA levels (2200%, p<0.001) measured by HPLC, which had been reduced by the antioxidants. Oxidative stress down‐regulated mRNA and protein expression of ABCA1, a transporter involved in cellular cholesterol efflux. Peroxidation stimulated mRNA expression without alteration of protein mass of SR‐B1, a scavenger receptor that usually enhances cholesterol uptake. In parallel, experiments performed on cholesterol transport showed that peroxidation reduces cholesterol efflux without altering the influx process. Experiments using RT‐PCR showed that these modulations are orchestrated by the nuclear receptors LXRα, LXRβ, PPARα and PPARγ. Overall, our results demonstrated that oxidative stress modulates receptor and signalling pathways in THP‐1 macrophages, thus inhibiting cholesterol efflux, which could stimulate foam cell formation and atherosclerosis development.