Conjugated linoleic acid and atherosclerosis: no effect on molecular markers of cholesterol homeostasis in THP-1 macrophages.
Macrophage cholesterol homeostasis is a key process involved in the initiation and progression of atherosclerosis. Peroxisome proliferator-activated receptors (PPARs) regulate the transcription of the genes involved in cholesterol homeostasis and thus represent an important therapeutic target in terms of reducing atherosclerosis. Conjugated linoleic acid (CLA) is a potent anti-atherogenic dietary fatty acid in animal models of atherosclerosis and is capable of activating PPARs in vitro and in vivo. Therefore, this study examined whether the anti-atherogenic effects of CLA in vivo could be ascribed to altered cholesterol homeostasis in macrophages and macrophage derived foam cells. Of several genes that regulate cholesterol homeostasis investigated, CLA had most effect on the class B scavenger receptor CD36. The cis-9,trans-11 CLA (c9,t11-CLA) and trans-10,cis-12 CLA (t10,c12-CLA) isomers augmented CD36 mRNA expression (P<0.001). Confocal laser microscopy characterised the three-dimensional expression patterns of CD36 in THP-1 macrophages. Linoleic acid, CLA and the PPARgamma ligand rosiglitazone increased discrete cell surface CD36 localisation, with a heterogeneous punctate pattern of expression. In agreement with the observed increases in CD36 mRNA and cell surface expression, intracellular cholesterol concentrations were greater in macrophages exposed to linoleic acid and CLA. Further analysis of cholesterol metabolism showed that CLA had no effect on THP-1 derived foam cell cholesterol efflux to apo AI. Thus, altered cholesterol homeostasis in the macrophage may not explain the anti-atherogenic effects of CLA observed in vivo.
Weldon
Sinéad
S
Department of Clinical Medicine, Unit of Nutrition, Trinity Centre for Health Sciences, St James's Hospital, James's Street, Dublin 8, Ireland.
Mitchell
Siobhan
S
Kelleher
Dermot
D
Gibney
Michael J
MJ
Roche
Helen M
HM
D000704:Analysis of Variance; D001161:Arteriosclerosis / Q000503:physiopathology*; D015415:Biomarkers / Q000032:analysis; D018955:CD36 Antigens / Q000032:analysis / Q000235:genetics; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D005487:Foam Cells / Q000187:drug effects* / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D019787:Linoleic Acid / Q000494:pharmacology*; D008264:Macrophages / Q000378:metabolism; D018613:Microscopy, Confocal; D012313:RNA / Q000032:analysis; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity
D015415:Biomarkers; D018955:CD36 Antigens; D012313:RNA; D002784:Cholesterol; D019787:Linoleic Acid