Triglyceride-rich lipoproteins inhibit cholesterol efflux to apolipoprotein (apo) A1 from human macrophage foam cells

  • Anna M Palmer
    Corresponding author. Present address: Hugh Sinclair Unit of Human Nutrition, School of Food Biosciences, The University of Reading, P.O. Box 226, Reading RG6 6AP, UK. Tel.: +44-118-378-8727; fax: +44-118-931-8703.
    Department of Biochemistry and Molecular Biology, Royal Free and University College Medical School, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK
    Search for articles by this author
  • Nuala Murphy
    Department of Biochemistry and Molecular Biology, Royal Free and University College Medical School, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK
    Search for articles by this author
  • Annette Graham
    Department of Biochemistry and Molecular Biology, Royal Free and University College Medical School, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK
    Search for articles by this author


      High circulating levels of triglyceride-rich lipoproteins (TGRL) represent an independent risk factor for coronary artery disease. Here, we show that TGRL inhibit the efflux of cholesterol from ‘foam cell’ macrophages to lipid-poor apolipoprotein (apo) A1, and may thereby inhibit arterial reverse cholesterol transport and promote the formation of atherosclerotic lesions. Human (THP-1) monocyte-derived macrophages were pre-incubated (48 h) with acetylated low-density lipoprotein (AcLDL) to provide a foam cell model of cholesterol efflux to apoA1. Pre-incubation of macrophage ‘foam cells’ with TGRL (0–200 μg/ml, 0–24 h) inhibited the efflux of exogenously radiolabelled ([Math Eq]), endogenously synthesised ([Math Eq]) and cellular cholesterol mass to lipid-poor apoA1, but not control medium, during a (subsequent) efflux period. This inhibition is dependent upon the length of prior exposure to, and concentration of, TGRL employed, but is independent of changes in intracellular triglyceride accumulation or turnover of the cholesteryl ester pool. Despite the negative impact of TGRL on cholesterol efflux, major proteins involved in this process—namely apoE, ABCA1, SR-B1 and caveolin-1—were unaffected by TGRL pre-incubation, suggesting that exposure to these lipoproteins inhibits an alternate, and possibly novel, anti-atherogenic pathway.


      ABC (ATP binding cassette), AcLDL (acetylated low-density lipoprotein), apo (apolipoprotein), BSA (bovine serum albumin), CAV-1 (caveolin-1), CE (cholesteryl ester), SR-B1 (scavenger receptor-B1), TG (triglyceride/triacylglycerol), TGRL (triglyceride-rich lipoproteins)


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Tkac I
        • Kimball B.P
        • Lewis G
        • Uffelman K
        • Steiner G
        The severity of coronary atherosclerosis in type II diabetes mellitus is related to the number of circulating triglyceride-rich lipoprotein particles.
        Arterioscler. Thromb. Vasc. Biol. 1997; 17: 3633-3638
        • Mahley R.W
        • Weisgraber K.H
        • Innerarity L
        • Rall S.C
        Genetic defects in lipoprotein metabolism. Elevation of atherogenic lipoproteins caused by impaired catabolism.
        J. Am. Med. Assoc. 1991; 265: 78-83
        • de Graaf J
        • Stalenhoef A.F.H
        Defects of lipoprotein metabolism in familial combined hyperlipidaemia.
        Curr. Opin. Lipidol. 1998; 9: 189-196
        • Hokanson J.E
        • Austin M.A
        Plasma triglyceride level is a risk factor for cardiovascular disease independent of high density lipoprotein cholesterol levels: a meta-analysis of population-based prospective studies.
        J. Cardiovasc. Risk. 1996; 3: 213-219
        • Packard C.J
        • Petrie J.R
        The end of triglycerides in cardiovascular risk assessment?.
        Br. Med. J. 1998; 317: 553-554
        • Mamo J.C.L
        • Wheeler J.R
        Chylomicrons or their remnants penetrate rabbit thoracic aorta as efficiently as smaller macromolecules, including low density lipoprotein, high density lipoprotein and albumin.
        Coron. Artery Dis. 1994; 5: 695-705
        • Rapp J.H
        • Lespine A
        • Hamilton R.L
        • Colyvas N
        • Chaumeton A.H
        • Tweedie-Hardman J
        • et al.
        Triglyceride-rich lipoproteins isolated by selected-affinity anti-apolipoprotein B immunosorption from human atherosclerotic plaque.
        Arterioscler. Thromb. 1994; 14: 1767-1774
        • Proctor S.D
        • Mamo J.C.L
        Retention of fluorescent-labelled chylomicron remnants within the intima of the arterial wall—evidence that plaque cholesterol may be derived from post-prandial lipoproteins.
        Eur. J. Clin. Invest. 1998; 28: 497-503
        • Sattar N
        • Petrie J.R
        • Jaap A.J
        The atherogenic lipoprotein phenotype and vascular endothelial dysfunction.
        Atherosclerosis. 1998; 138: 229-235
        • Carantoni M
        • Abbasi F
        • Chu L
        • Chen Y.D.I
        • Reaven G.M
        • Taso P.S
        • et al.
        Adherence of mononuclear cells to endothelium in vitro is increased in patients with NIDDM.
        Diabetes Care. 1997; 20: 1462-1465
        • Bates S.R
        • Murphy P.L
        • Feng Z
        • Kanazawa T
        • Getz G.S
        Very low density lipoproteins promote triglyceride accumulation in macrophages.
        Arteriosclerosis. 1984; 4: 103-114
        • Saito M
        • Eto M
        • Okada M
        • Iwashima Y
        • Makino I
        Remnant-like particles (RLP) from NIDDM patients with apolipoprotein E3/E3 phenotype stimulated cholesteryl ester synthesis in human monocyte-derived macrophages.
        Artery. 1996; 22: 155-163
        • Fujioka Y
        • Cooper A.D
        • Fong L.G
        Multiple processes are involved in the uptake of chylomicron remnants by mouse peritoneal macrophages.
        J. Lipid Res. 1998; 39: 2339-2349
      1. Fredrickson DS, Goldstein JL, Brown MS. The familial hyperlipoproteinaemias. In: Stanbury JG, Wyngaarden MF, Fredrickson DS, editors. The metabolic basis of inherited diseases. New York: McGraw-Hill; 1978. p. 604–44.

        • Parker F
        • Bagdade J.D
        • Odland G.F
        • Bierman E.L
        Evidence for the chylomicron origin of lipids accumulating in diabetic eruptive xanthomas: a correlative lipid biochemical.
        J. Clin. Invest. 1970; 49: 2172-2187
        • Cavallero E
        • Brites F
        • Delfly B
        • Nicolaiew N
        • Decossin C
        • De Geitere C
        • et al.
        Abnormal reverse cholesterol transport in controlled type II diabetic patients.
        Arterioscler. Thromb. Vasc. Biol. 1995; 15: 2130-2135
        • Syvanne M
        • Castro G
        • Dengremont C
        • De Geitere C
        • Jauhaininen M
        • Ehnholm C
        • et al.
        Cholesterol efflux from Fu5AH hepatoma cells induced by plasma of subjects with or without coronary artery disease and non-insulin dependent diabetes: importance of LpA-I:A-II particles and phospholipid transfer protein.
        Atherosclerosis. 1996; 127: 245-253
        • Syvanne M
        • Ahola M
        • Lahdenpera S
        • Kahri J
        • Kuusi T
        • Virtanen K.S
        • et al.
        High density lipoprotein subfractions in non-insulin dependent diabetes mellitus and coronary artery disease.
        J. Lipid Res. 1995; 36: 573-582
        • Rader D.J
        • Maugeais C
        Genes influencing HDL metabolism: new perspectives and implications for atherosclerosis prevention.
        Mol. Med. Today. 2000; 6: 170-175
        • Rubin E.M
        • Krauss R.M
        • Spangler E.A
        • Verstuyft J.G
        • Clift S.M
        Inhibition of early atherogenesis in transgenic mice by human apolipoprotein A1.
        Nature. 1991; 353: 265-267
        • Pastzy C
        • Maeda N
        • Verstuyft J
        • Rubin E.M
        Apolipoprotein A1 transgene corrects apolipoprotein E deficiency-induced atherosclerosis in mice.
        J. Clin. Invest. 1994; 94: 899-903
        • Lindholm E.M
        • Palmer A.M
        • Graham A
        Triglyceride-rich lipoproteins alter the secretion, and cholesterol effluxing function, of apolipoprotein E-containing lipoprotein particles from human (THP-1) macrophages.
        Biochem. J. 2001; 356: 515-523
        • Ho Y.K
        • Brown M.S
        • Goldstein J.L
        Hydrolysis and excretion of cytoplasmic cholesteryl esters by macrophages: stimulation by high density lipoprotein and other agents.
        J. Lipid Res. 1980; 21: 391-398
        • Arakawa R
        • Abe-Dohmae S
        • Asai M
        • Ito J
        • Yokoyama S
        Involvement of caveolin-1 in cholesterol enrichment of high density lipoprotein during its assembly by apolipoprotein and THP-1 cells.
        J. Lipid Res. 2000; 41: 1952-1962
        • Bodzioch M
        • Orso E
        • Klucken J
        • Langmann T
        • Bottcher A
        • Diederich W
        • et al.
        The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease.
        Nat. Genet. 1999; 22: 347-351
        • Brooks-Wilson A
        • Marcil M
        • Clee S.M
        • Zhang L.-H
        • Roomp K
        • van Dam M
        • et al.
        Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency.
        Nat. Genet. 1999; 22: 336-345
        • Rust S
        • Rosier M
        • Funke H
        • Real J
        • Amoura Z
        • Piette J.-C
        • et al.
        Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1.
        Nat. Genet. 1999; 22: 352-355
        • Langmann T
        • Klucken J
        • Reil M
        • Liebisch G
        • Luciani M.-F
        • Chimini G
        • et al.
        Molecular cloning of the human ATP-binding cassette transporter-1 (hABC1): evidence for sterol-dependent regulation in macrophages.
        Biochem. Biophys. Res. Commun. 1999; 257: 29-33
        • Klucken J
        • Buchler C
        • Orso E
        • Kaminski W.E
        • Porsch-Ozcurumez M
        • Liebisch G
        • et al.
        ABCG1 (ABC8), the human homolog of the Drosophila white gene, is a regulator of macrophage cholesterol and phospholipid transport.
        Proc. Natl. Acad. Sci. U.S.A. 2000; 97: 817-822
        • Kaminski W.E
        • Piehler A
        • Pullmann K
        • Porsch-Ozcurumez M
        • Duong C
        • Bared G.M
        • et al.
        Complete coding sequence, promoter region, and genomic structure of the human ABCA2 gene and evidence for sterol-dependent regulation in macrophages.
        Biochem. Biophys. Res. Commun. 2001; 281: 249-258
        • Kaminski W.E
        • Orso E
        • Diederich W
        • Klucken J
        • Drobnik W
        • Schmitz G
        Identification of a novel human sterol-sensitive ATP-binding cassette transporter (ABCA7).
        Biochem. Biophys. Res. Commun. 2000; 273: 532-538
        • Jian V
        • de la Llera-Moya M
        • Ji Y
        • Wang N
        • Phillips M.C
        • Swaney J.B
        • et al.
        Scavenger receptor class B type I as a mediator of cellular cholesterol efflux to lipoproteins and phospholipid acceptors.
        J. Biol. Chem. 1998; 273: 5599-5606
        • Chen W
        • Silver D.L
        • Smith J.D
        • Tall A.R
        Scavenger receptor-B1 inhibits ATP-binding cassette transporter-1 mediated cholesterol efflux in macrophages.
        J. Biol. Chem. 2000; 275: 30794-30800
        • Takahashi Y
        • Smith J.D
        Cholesterol efflux to apolipoprotein A1 involves endocytosis and resecretion in a calcium-dependent pathway.
        Proc. Natl. Acad. Sci. U.S.A. 1999; 96: 11358-11363
        • Mazzone T
        Apolipoprotein E secretion by macrophages: its potential physiological functions.
        Curr. Opin. Lipidol. 1996; 7: 303-307
        • Bielicki J.K
        • McCall M.R
        • Forte T.M
        Apolipoprotein A-I promotes cholesterol release and apolipoprotein E recruitment from THP-1 macrophage-like foam cells.
        J. Lipid Res. 1999; 40: 85-92
        • Rees D
        • Sloane T
        • Jessup W
        • Dean R.T
        • Kritharides L
        Apolipoprotein A-I stimulates secretion of apolipoprotein E by foam cell macrophages.
        J. Biol. Chem. 1999; 274: 27925-27933
        • Havel R.J
        • Eder H.A
        • Bragdon J.H
        The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum.
        J. Clin. Invest. 1955; 34: 1345-1353
        • Basu S.K
        • Anderson R.G
        • Goldstein J.L
        • Brown M.S
        Metabolism of cationised lipoprotein by human fibroblasts. Biochemical and morphologic correlations.
        J. Cell Biol. 1977; 74: 119-135
        • Bligh E.G
        • Dyer W.J
        A rapid method of total lipid extraction and purification.
        Can. J. Biochem. Physiol. 1959; 37: 911-917
        • Small C.A
        • Goodacre J.A
        • Yeaman S.J
        Hormone sensitive lipase is responsible for the neutral cholesterol ester hydrolase activity in macrophages.
        FEBS Lett. 1989; 247: 205-208
        • Reue K
        • Coeh R.D
        • Schotz M.C
        Evidence for hormone sensitive lipase mRNA in human macrophages.
        Arterioscler. Thromb. Vasc. Biol. 1997; 17: 3428-3432
        • Jepson C.A
        • Harrison J.A
        • Kraemer F.B
        • Yeaman S.J
        Down-regulation of hormone-sensitive lipase in sterol ester-laden J774.2 macrophages.
        Biochem. J. 1996; 318: 173-177
        • Graham A
        • Angell A.D.R
        • Jepson C.A
        • Yeaman S.Y
        • Hassall D.G
        Impaired mobilisation of cholesterol from stored cholesteryl esters in human (THP-1) macrophages.
        Atherosclerosis. 1996; 120: 135-145
        • Lada A.T
        • Willingham M.C
        • St. Clair R.W
        Triglyceride depletion in THP-1 cells alters cholesteryl ester physical state and cholesterol efflux.
        J. Lipid Res. 2002; 43: 618-628
        • Harte R.A
        • Hulten L.M
        • Lindmark H
        • Reue K
        • Schotz M.C
        • Khoo J
        • et al.
        Low level expression of hormone-sensitive lipase in arterial macrophage-derived foam cells: potential explanation for low rates of cholesteryl ester hydrolysis.
        Atherosclerosis. 2000; 149: 343-350
        • Auwerx J
        The human leukaemia cell line, THP-1: a multifacetted model for the study of monocyte-macrophage differentiation.
        Experientia. 1991; 47: 22-31
        • Chinetti G
        • Lestavel S
        • Bocher V
        • Remaley A.T
        • Neve B
        • Torra I.P
        • et al.
        PPAR-alpha and PPAR-gamma activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway.
        Nat. Med. 2001; 7: 53-58
        • Oliver W.R
        • Shenk J.L
        • Snaith M.R
        • Russell C.S
        • Plunket K.D
        • Bodkin N.L
        • et al.
        A selective peroxisome proliferator-activated receptor d agonist promotes reverse cholesterol transport.
        Proc. Natl. Acad. Sci. U.S.A. 2001; 98: 5306-5311
        • Matveev S
        • van der Westhuyzen D.R
        • Smart E.J
        Co-expression of scavenger receptor-B1 and caveolin-1 is associated with enhanced selective cholesteryl ester uptake in THP-1 macrophages.
        J. Lipid Res. 1999; 40: 1647-1654
        • Krieger M
        Charting the fate of the ‘good cholesterol’: identification and characterisation of the high-density lipoprotein receptor, SR-B1.
        Annu. Rev. Biochem. 1999; 68: 523-558
        • Garner B
        • Baoutina A
        • Dean R.T
        • Jessup W
        Regulation of serum-induced lipid accumulation in human monocyte-derived macrophages by interferon. Correlations with apolipoprotein E production, lipoprotein lipase activity and LDL receptor-related protein expression.
        Atherosclerosis. 1997; 128: 47-58
        • Fidge N
        High density lipoprotein receptors, binding proteins and ligands.
        J. Lipid Res. 1999; 40: 187-201
        • Walter M
        • Reinecke H
        • Gerdes U
        • Nofer J.-R
        • Hobbel G
        • Seedorf U
        • et al.
        Defective regulation of phosphatidylcholine-specific phospholipases C and D in a kindred with Tangier disease.
        J. Clin. Invest. 1996; 98: 2315-2323
        • Haidar B
        • Mott S
        • Boucher B
        • Lee C.Y
        • Marcil M
        • Genest J
        Cellular cholesterol efflux is modulated by phospholipid-derived signaling molecules in familial HDL deficiency/Tangier disease fibroblasts.
        J. Lipid Res. 2001; 42: 249-257
        • Utech M
        • Hobbel G
        • Rust S
        • Reinecke H
        • Assmann G
        • Walter M
        Accumulation of RhoA, RhoB, RhoG and Rac1 in fibroblasts from Tangier disease subjects suggests a regulatory role of Rho family proteins in cholesterol efflux.
        Biochem. Biophys. Res. Commun. 2001; 280: 229-236
        • Hirano K
        • Matsuura F
        • Tsukamoto K
        • Zhang Z
        • Matsuyama A
        • Takaishi K
        • et al.
        Decreased expression of a member of the Rho GTPase family, Cdc42Hs, in cells from Tangier disease—the small G protein may play a role in cholesterol efflux.
        FEBS Lett. 2000; 484: 275-279