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Conjugated linoleic acid and atherosclerosis: no effect on molecular markers of cholesterol homeostasis in THP-1 macrophages

  • Sinéad Weldon
    Affiliations
    Nutrigenomics Research Groups, Department of Clinical Medicine, Unit of Nutrition, Trinity Centre for Health Sciences, St. James’s Hospital, James’s Street, Dublin 8, Ireland
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  • Siobhan Mitchell
    Affiliations
    Immunology Research Groups, Department of Clinical Medicine, Unit of Nutrition, Trinity Centre for Health Sciences, St. James’s Hospital, Dublin 8, Ireland
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  • Dermot Kelleher
    Affiliations
    Immunology Research Groups, Department of Clinical Medicine, Unit of Nutrition, Trinity Centre for Health Sciences, St. James’s Hospital, Dublin 8, Ireland
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  • Michael J Gibney
    Affiliations
    Nutrigenomics Research Groups, Department of Clinical Medicine, Unit of Nutrition, Trinity Centre for Health Sciences, St. James’s Hospital, James’s Street, Dublin 8, Ireland
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  • Helen M Roche
    Correspondence
    Corresponding author. Tel.: +353-1-6082481; fax: +353-1-4542043.
    Affiliations
    Nutrigenomics Research Groups, Department of Clinical Medicine, Unit of Nutrition, Trinity Centre for Health Sciences, St. James’s Hospital, James’s Street, Dublin 8, Ireland
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      Abstract

      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 PPARγ 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.

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      References

        • Ross R
        Atherosclerosis—an inflammatory disease.
        N. Engl. J. Med. 1999; 340: 115-126
        • Barbier O
        • Pineda Torra I
        • Duguay Y
        • et al.
        Pleiotropic actions of peroxisome proliferator-activated receptors in lipid metabolism and atherosclerosis.
        Arterioscler Thromb. Vasc. Biol. 2002; 22: 717-726
        • Duval C
        • Chinetti G
        • Trottein F
        • Fruchart J.-C
        • Staels B
        The role of PPARs in atherosclerosis.
        Trends Mol. Med. 2002; 8: 422-430
        • Kersten S
        • Desvergne B
        • Wahli W
        Roles of PPARs in health and disease.
        Nature. 2000; 405: 421-424
        • Tontonoz P
        • Nagy L
        • Alvarez J.G.A
        • Thomazy V.A
        • Evans R.M
        PPARγ promotes monocyte/macrophage differentiation and uptake of oxidised LDL.
        Cell. 1998; 93: 241-252
        • Steinberg D
        Atherogenesis in perspective: hypercholesterolemia and inflammation as partners in crime.
        Nat. Med. 2002; 8: 1211-1217
        • Moore K.J
        • Rosen E.D
        • Fitzgerald M.L
        • et al.
        The role of PPAR-γ in macrophage differentiation and cholesterol uptake.
        Nat. Med. 2001; 7: 41-47
        • Chinetti G
        • Lestavel S
        • Bocher V
        • et al.
        PPAR-α and PPAR-γ activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway.
        Nat. Med. 2001; 7: 53-58
        • Klucken J
        • Büchler C
        • Orsó E
        • et al.
        ABCG1 (ABC8), the human homolog of the Drosophila white gene, is a regulator of macrophage and phospholipid transport.
        Proc. Natl. Acad. Sci. U.S.A. 2000; 97: 817-822
        • Chawla A
        • Boisvert W.A
        • Lee C.-H
        • et al.
        A PPAR γ-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis.
        Mol. Cell. 2001; 7: 161-171
        • Akiyama T.E
        • Sakai S
        • Lambert G
        • et al.
        Conditional disruption of the peroxisome proliferator-activated receptor γ gene in mice results in lowered expression of ABCA1, ABCG1, and apoE in macrophages and reduced cholesterol efflux.
        Mol. Cell Biol. 2002; 22: 2607-2619
        • Vosper H
        • Khoudoli G.A
        • Graham T.L
        Palmer CNA. Peroxisome proliferator-activated receptor agonists, hyperlipidaemia, and atherosclerosis.
        Pharmacol. Ther. 2002; 5492: 1-16
        • Moya-Camarena S.Y
        • Vanden Heuvel J.P
        • Blanchard S.G
        • Leesnitzer L.A
        • Belury M.A
        Conjugated linoleic acid is a potent naturally occurring ligand and activator of PPARα.
        J. Lipid Res. 1999; 40: 1426-1433
        • Yu Y
        • Corell P.H
        • Vanden Heuvel J.P
        Conjugated linoleic acid decreases production of pro-inflammatory products in macrophages: evidence for a PPARγ-dependent mechanism.
        Biochim. Biophys. Acta. 2002; 1581: 89-99
        • Toomey S
        • Roche H
        • Fitzgerald D
        • Belton O
        Regression of pre-established atherosclerosis in the apoE−/− mouse by conjugated linoleic acid.
        Biochem. Soc. Trans. 2003; 31: 1075-1079
        • Kritchevsky D
        • Tepper S.A
        • Wright S
        • Tso P
        • Czarnecki S.K
        Influence of conjugated linoleic acid (CLA) on establishment and progression of atherosclerosis in rabbits.
        J. Am Coll. Nutr. 2000; 19: 472S-477S
        • Munday J.S
        • Thompson K.G
        • James K.A.C
        Dietary conjugated linoleic acids promote fatty streak formation in the C57BL/6 mouse atherosclerosis model.
        Br J. Nutr. 1999; 81: 251-255
        • Roche H.M
        • Noone E
        • Sewyer C
        • et al.
        Isomer-dependent effects of conjugated linoleic acid. Insights from molecular markers sterol regulatory element-binding protein-1c and LXRα.
        Diabetes. 2002; 51: 2037-2044
        • Park Y
        • Pariza M.W
        Evidence that commercial calf and horse sera can contain substantial amounts of trans-10,cis-12 conjugated linoleic acid.
        Lipids. 1998; 33: 817-819
        • Noone E.J
        • Roche H.M
        • Nugent A.P
        • Gibney M.J
        The effect of dietary supplementation using isomeric blends of conjugated linoleic acid on lipid metabolism in healthy human subjects.
        Br J. Nutr. 2002; 88: 243-251
        • Tada Iida K
        • Kawakami Y
        • Suzuki H
        • et al.
        PPARγ ligands, troglitazone and pioglitazone, up-regulate expression of HMG-CoA synthase and HMG-CoA reductase gene in THP-1 macrophages.
        FEBS Lett. 2002; 520: 177-181
        • Folch J
        • Lees M
        • Sloane Stanley G.H
        A simple method for the isolation and purification of total lipides from animal tissues.
        J. Biol. Chem. 1957; 226: 497-509
        • Jiang J
        • Wolk A
        • Vessby B
        Relation between the intake of milk fat and the occurrence of conjugated linoleic acid in human adipose tissue.
        Am J. Clin. Nutr. 1999; 70: 21-27
        • Glass C.K
        • Witztum J.L
        Atherosclerosis: the road ahead.
        Cell. 2001; 104: 503-516
        • Auwerx J
        The human leukemia cell line, THP-1: a multifacetted model for the study of monocyte-macrophage differentiation.
        Experientia. 1991; 47: 22-31
        • Kritharides L
        • Christian A
        • Stoudt G
        • Morel D
        • Rothblat G.H
        Cholesterol metabolism and efflux in human THP-1 macrophages.
        Arterioscler. Thromb. Vasc. Biol. 1998; 18: 1589-1599
        • Febbraio M
        • Hajjar D.P
        • Silverstein R.L
        CD36: a class B scavenger receptor involved in angiogenesis, atherosclerosis, inflammation, and lipid metabolism.
        J. Clin. Invest. 2001; 108: 785-791
        • Febbraio M
        • Podrez E.A
        • Smith J.D
        • et al.
        Targeted disruption of the class B scavenger receptor CD36 protects against atherosclerotic lesion development in mice.
        J. Clin. Invest. 2000; 105: 1049-1056
        • Pietsch A
        • Weber C
        • Goretzki M
        • Weber P.C
        • Lorenz R.L
        N-3 but not N-6 fatty acids reduce the expression of the combined adhesion and scavenger receptor CD36 in human monocytic cells.
        Cell Biochem. Funct. 1995; 13: 211-216
        • Vallvé J.-C
        • Uliaque K
        • Girona J
        • et al.
        Unsaturated fatty acids and their oxidation products stimulate CD36 gene expression in human macrophages.
        Atherosclerosis. 2002; 164: 45-56
        • Svensson L
        • Camejo G
        • Cabré A
        • et al.
        Fatty acids modulate the effect of darglitazone on macrophage CD36 expression.
        Eur. J. Clin. Invest. 2003; 33: 464-471
        • Chinetti G
        • Lestavel S
        • Fruchart J.-C
        • Clavey V
        • Staels B
        Peroxisome proliferator-activated receptor a reduced cholesterol esterification in macrophages.
        Circ. Res. 2003; 92: 212-217
        • Moya-Camarena S.Y
        • Belury M.A
        Species differences in the metabolism and regulation of gene expression by conjugated linoleic acid.
        Nutr. Rev. 1999; 57: 336-340
        • Black I.L
        • Roche H.M
        • Gibney M.J
        Chronic but not acute treatment with conjugated linoleic acid (CLA) isomers (trans-10, cis-12 CLA and cis-9, trans-11 CLA) affects lipid metabolism in Caco-2 cells.
        J. Nutr. 2001; 132: 2167-2173