Skip to main content
SpringerLink
Log in

Chylomicron remnants and oxidised low density lipoprotein have differential effects on the expression of mRNA for genes involved in human macrophage foam cell formation

  • Original Article
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

The effects of chylomicron remnants (non-oxidised or oxidised) and oxidised low density lipoprotein (oxLDL) on the expression of mRNA for a wide range of genes believed to play a role in macrophage foam cell formation were compared using macrophages derived from the human monocyte cell line THP-1. Chylomicron remnant-like particles (CMR-LPs), oxidised CMR-LPs (oxCMR-LPs) and oxLDL were incubated with THP-1 macrophages, and the relative abundance of mRNA transcripts for genes involved in lipoprotein uptake, intracellular lipid metabolism, transport and storage and cholesterol efflux from macrophages was determined. The results show that CMR-LPs and oxLDL differ markedly in their effects on the expression of mRNA for a number of the genes tested. OxLDL increased mRNA levels for the scavenger receptors CD36 (×3.2) and lectin-like oxLDL receptor 1 (×2.1), and peroxisome proliferator-activated receptor γ while CMR-LPs did not. In contrast, the expression of mRNA for the LDL receptor-like protein was raised by CMR-LPs (×1.8) but not oxLDL. Furthermore, down-regulation of mRNA levels for the ATP-binding cassette transporter (ABC) A1 was observed with CMR-LPs (×0.6), compared to the up-regulation found with oxLDL (×4.4). In addition, a number of significant differences were found between the effects of CMR-LPs and oxCMR-LPs, with the oxidised particles causing a striking rise in mRNA expression for the multi-drug resistance 1 gene (×13.7), but otherwise showing pattern more similar to that seen with oxLDL. These findings provide evidence to indicate that chylomicron remnants cause lipid accumulation in macrophages by influencing the expression of genes which regulate lipid metabolism at the transcriptional level, and that the mechanisms involved differ in important respects from those triggered by oxLDL.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

ABC :

ATP-binding cassette transporter

ACAT :

Co-enzyme A:cholesterol acyltransferase

ACBP :

Co-enzyme A binding protein

apoE :

Apolipoprotein E

CETP :

Cholesteryl ester transfer protein

CMR-LP :

Chylomicron remnant-like particle

FBS :

Foetal bovine serum

HMDM :

Human monocyte-derived macrophage

HMG-CoA :

3-Hydroxy-3 methylglutaryl co-enzyme A

HSL :

Hormone-sensitive lipase

LDL :

Low-density lipoprotein

LDLr :

LDL receptor

LOX :

Lectin-like oxLDL receptor

LPL :

Lipoprotein lipase

LRP :

Low-density lipoprotein receptor-like protein

MDR :

Multi-drug resistance

nCEH :

Cholesteryl ester hydrolase

ox- :

Oxidised

PBS :

Phosphate-buffered saline

PCR :

Polymerase chain reaction

PMA :

Phorbol 12-myristate 13-acetate

PPAR :

Peroxisome proliferator-activated receptor

RT :

Reverse transcriptase

SR :

Scavenger receptor

TG :

Triacylglycerol

References

  1. Ross R (1993) The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 362:801–809

    CAS  PubMed  Google Scholar 

  2. Chisholm GM, Steinberg D (2000) The oxidative modification hypothesis of atherogenesis: an overview. Free Radic Biol Med 28:1815–1826

    Article  CAS  PubMed  Google Scholar 

  3. Napolitano M, Rivabene R, Avella M, Botham KM, Bravo E (2001) The internal redox balance of cells influences the metabolism of lipids of dietary origin by J774 macrophages: implications for foam cell formation. J Vasc Res 38:350–360

    Article  CAS  PubMed  Google Scholar 

  4. Batt KV, Avella M, Moore EH, Jackson B, Suckling KE, Botham KM (2004) Differential effects of low density lipoprotein and chylomicron remnants on lipid accumulation in human macrophages. Exp Biol Med (in press)

  5. Yu KC, Mamo JC (2000) Chylomicron remnant-induced foam cell formation and cytotoxicity: a possible mechanism of cell death in atherosclerosis. Clin Sci (Colch) 98:183–192

    Google Scholar 

  6. Redgrave TG (1983) Formation and metabolism of chylomicrons. Int Rev Physiol 28:103–130

    CAS  PubMed  Google Scholar 

  7. Yu KC, Cooper AD (2001) Postprandial lipoproteins and atherosclerosis.Front Biosci 6:D332–D354

    CAS  PubMed  Google Scholar 

  8. Proctor SD, Vine DF, Mamo JC (2002) Arterial retention of apolipoprotein B (48)- and B (100)-containing lipoproteins in atherogenesis. Curr Opin Lipidol 13:461–470

    Article  CAS  PubMed  Google Scholar 

  9. Mamo JCL, Wheeler JR (1994) Chylomicrons or their remnants penetrate rabbit thoracic aorta as efficiently as do smaller macromolecules, including low density lipoprotein, high density lipoprotein and albumin. Coron Artery Dis 5:695–705

    CAS  PubMed  Google Scholar 

  10. Yla-Herttuala S, Jaakkola O, Enholm C, Tikkanen MJ, Solakivi T, Sarkioja T, Nikkari T (1988) Characterisation of two lipoproteins containing apolipoproteins B and E from lesion-free human aortic intima. J Lipid Res 29:563–572

    CAS  PubMed  Google Scholar 

  11. Rapp JH, Lespine A, Hamilton RL, Colyvas N, Chaumeton AH, Tweedie-Harman J, Kotite L, Kunitake ST, Havel RJ, Kane JP (1994) Triglyceride-rich lipoproteins isolated by selective affinity anti-apolipoprotein B immunosorption from human atherosclerotic plaque. Arterioscler Thromb 14:1767–1774

    CAS  PubMed  Google Scholar 

  12. Napolitano M, Avella M, Botham KM, Bravo E (2003) Chylomicron remnant induction of lipid accumulation in J774 macrophages is associated with up-regulation of triacylglycerol synthesis which is not dependent on oxidation of the particles. Biochim Biophys Acta 1631:255–264

    Article  CAS  PubMed  Google Scholar 

  13. Chinetti G, Gbaguidi FG, Griglio S, Mallat Z, Antonucci M, Poulain P, Chapman J, Fruchart J-C, Tedgui A, Najib-Fruchart J, Staels B (2000) CLA-1/SR-B1 is expressed in atherogenic lesion macrophages and regulated by activators of peroxisome proliferator-activated receptors. Circulation 101:2411–2417

    Google Scholar 

  14. Elsegood CL, Pal S, Roach PD, Mamo JC (2001) Binding and uptake of chylomicron remnants by primary and THP-1 monocyte-derived macrophages: determination of binding proteins. Clin Sci (Colch) 101:111–119

    Google Scholar 

  15. Oram JF (2002) ATP-binding cassette transporter A1 and cholesterol trafficking. Curr Opin Lipidol 13:373–381

    Google Scholar 

  16. Larkin L, Khachigian LM, Jessup W (2000) Regulation of apolipoprotein E production in macrophages (review). Int J Mol Med 6:253–258

    CAS  PubMed  Google Scholar 

  17. Zhang Z, Yamashita S, Hirano K, Nkagawa-Toyama Y, Matsuyama A, Nishida M, Sakai N, Fukusawa M, Arai H, Miyagawa J, Matsuzawa Y (2001) Expression of cholesteryl ester transfer protein in human atherosclerotic lesions and its implication in reverse cholesterol transport. Atherosclerosis 159:65–75

    Article  Google Scholar 

  18. Rudney H, Sexton RC (1986) Regulation of cholesterol biosynthesis. Annu Rev Nutr 6:245–272

    Article  CAS  PubMed  Google Scholar 

  19. Chang T-Y, Chang CCY, Lin S, Yu C, Li B-L, Miyazaki A (2001) Roles of acyl Co-enzyme A: cholesterol acyltransferase-1 and -2. Curr Opin Lipidol 12:289–296

    Article  CAS  PubMed  Google Scholar 

  20. Johnson WJ, Jang SY, Bernard DW (2000) Hormone sensitive lipase mRNA in both monocyte and macrophage forms of the human THP-1 cell line. Comp Biochem Physiol B Biochem Mol Biol 126:543–552

    Article  CAS  PubMed  Google Scholar 

  21. Stengel D, Antonucci M, Gaoua W, Dachet C, Lesnik P, Hourton D, Ninio E, Chapman MJ, Griglio S (1998) Inhibition of LPL expression in human monocyte-derived macrophages is dependent on LDL oxidation state: a key role for lysophosphatidylcholine. Arterioscler Thromb Vasc Biol 18:1172–1180

    Google Scholar 

  22. Kerkhoff C, Beuck M, Threige-Rasmussen J, Spener F, Knudsen J, Schmitz G (1997) Acyl CoA binding protein (ACBP) regulates acylCoA: cholesterol acyltransferase (ACAT) in human mononuclear phagocytes. Biochim Biophys Acta 1346:163–172

    Article  CAS  PubMed  Google Scholar 

  23. Matveev S, Li X, Everson W, Smart EJ (2001) The role of caveolae and caveolin in vesicle-dependent and vesicle-independent trafficking. Adv Drug Deliv Rev 49:237–250

    Article  CAS  PubMed  Google Scholar 

  24. Tessner TG, Stenson WF (2000) Overexpression of MDR1 in an intestinal cell line results in increased cholesterol uptake from micelles. Biochem Biophys Res Commun 267:565–571

    Article  CAS  PubMed  Google Scholar 

  25. Londos C, Brasaemle DL, Schultz CJ, Segrest JP, Kimmel AR (1999) Perilipins, ADRP, and other proteins that associate with intracellular neutral lipid droplets in animal cells. Semin Cell Dev Biol 10:51–58

    Google Scholar 

  26. Barbier O, Torra IP, Duguay Y, Blanquart C, Fruchart JC, Glineur C, Staels B (2002) Pleiotropic actions of peroxisome proliferator-activated receptors in lipid metabolism and atherosclerosis. Arterioscler Thromb Vasc Biol 22:717–726

    Article  CAS  PubMed  Google Scholar 

  27. Diard P, Malewiak M-I, Lagrange D, Griglio S (1994) Hepatic lipase may act as a ligand in the uptake of artificial chylomicron remnant-like particles by isolated rat hepatocytes. Biochem J 299:889–894

    CAS  PubMed  Google Scholar 

  28. Goulter AB, Avella MA, Elliott J, Botham KM (2002) Chylomicron remnant-like particles inhibit receptor-mediated endothelium-dependent vasorelaxation in porcine coronary arteries. Clin Sci (London) 103:450–460

    Google Scholar 

  29. Steinbrecher UP, Parthasarathy S, Leake DS, Witzum JL, Steinberg D (1984) Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids. Proc Natl Acad Sci USA 81:3883–3887

    CAS  PubMed  Google Scholar 

  30. Tsukamoto K, Kinoshita M, Kojima K, Mikuni Y, Kudo M, Mori M, Fujita M, Horie E, Shimazu N, Teramoto T (2002) Synergically increased expression of CD36, CLA-1 and CD68, but not of SR-A and LOX-1, with the progression to foam cells of macrophages. J Atheroscler Thrombolysis 9:57–64

    CAS  Google Scholar 

  31. Auwerx JH, Deeb S, Brunzell JD, Peng R, Chait AD (1988) Transcriptional activation of the lipoprotein lipase and apolipoprotein E genes accompanies differentiation in some human macrophage cell lines. Biochemistry 27:2651–2655

    CAS  PubMed  Google Scholar 

  32. Wang H, Germain SJ, Benfield PP, Gillies PJ (1996) Gene expression of acyl-coenzyme A: cholesterol acyltransferase is upregulated in human monocytes during differentiation and foam cell formation. Arterioscler Thromb Vasc Biol 16:809–814

    CAS  PubMed  Google Scholar 

  33. Langmann T, Schumacher C, Morham SG, Honer C, Heimerl S, Moehle C, Schmitz G (2003) ZNF202 is inversely regulated with its target genes ABCA1 and apoE during macrophage differentiation and foam cell formation. J Lipid Res 44:968–977

    Article  CAS  PubMed  Google Scholar 

  34. Perez A, Thuillard JL, Bentzen CL, Niesor EJ (2003) Expression of nuclear receptors and apoE secretion during differentiation of monocytic THP-1 cells into macrophages. Cell Biol Toxicol 19:95–105

    Article  CAS  PubMed  Google Scholar 

  35. Watanabe Y, Inaba T, Shimano H, Gotoda T, Yamamoto K, Mokuno H, Sato H, Yazaki T, Yamada N (1994) Induction of LDL receptor-related protein during the differentiation of monocyte-macrophages. Possible involvement in the atherosclerotic process. Arterioscler Thromb 14:1000–1006

    CAS  PubMed  Google Scholar 

  36. Auwerx J (1991) The human leukemia cell line, THP-1: a multifacetted model for the study of monocyte-macrophage differentiation. Experientia 47:22–31

    CAS  PubMed  Google Scholar 

  37. Sultan F, Lagrange D, Le Liepvre X, Griglio S (1989) Chylomicron remnant uptake by freshly isolated hepatocytes. Effects of heparin and of hepatic triacylglycerol lipase. Biochem J 258:587–594

    CAS  PubMed  Google Scholar 

  38. Brown MS, Goldstein JL (1983) Lipoprotein metabolism in the macrophage: implications for foam cell formation. Annu Rev Biochem 52:223–261

    Google Scholar 

  39. Rolhmann A, Gotthardt M, Hammer RE, Herz J (1998) Inducible activation of the hepatic LRP gene by cre-mediated recombination confirms role of LRP in clearance of chylomicron remnants. J Clin Invest 101:689–695

    CAS  PubMed  Google Scholar 

  40. Mahley RW, Ji ZS (1999) Remnant lipoprotein metabolism: key pathways involving cell-surface heparan sulfate proteoglycans and apolipoprotein E. J Lipid Res 40:1–16

    CAS  PubMed  Google Scholar 

  41. Han J, Hajjar DP, Febbraio M, Nicholson AC (1997) Native and modified low density lipoproteins increase the functional expression of the macrophage class B scavenger receptor. J Biol Chem 272:21654–21659

    Article  CAS  PubMed  Google Scholar 

  42. Osterud B, Bjorklid E (2003) Role of monocytes in atherogenesis. Physiol Rev 83:1069–1112

    CAS  PubMed  Google Scholar 

  43. Kume N, Kita T (2001) Roles of lectin-like oxidized LDL recptor-1 and its soluble forms in atherogenesis. Curr Opin Lipidol 12:419–423

    Article  CAS  PubMed  Google Scholar 

  44. Ghosh S (2000) Cholesteryl ester hydrolase in human monocyte/macrophage: cloning, sequencing and expression of full length DNA. Physiol Genomics 2:1–8

    CAS  PubMed  Google Scholar 

  45. Contreras JA (2002) Hormone-sensitive lipase is not required for cholesteryl ester hydrolysis in macrophages. Biochem Biophys Res Commun 292:900–903

    Article  CAS  PubMed  Google Scholar 

  46. Batetta B, Dessi S, Putzolu M, Sanna F, Spano O, Mulas F, Petruzzo P, Cappai A, Brotzu G (1999) MDR1 gene expression in normal and atherosclerotic human arteries. J Vasc Res 36:261–271

    Article  CAS  PubMed  Google Scholar 

  47. Wang X, Reape TJ, Rayner K, Webb CL, Burnard KG, Lysko PG (1999) Induced expression of adipophilin mRNA in human macrophages stimulated with oxidized low-density lipoprotein. FEBS Lett 462:145–150

    Article  CAS  PubMed  Google Scholar 

  48. Kielar D, Dietmaier W, Langmann T, Aslanidis C, Probst M, Naruszewicz M, Schmitz G (2001) Rapid quantification of human ABCA1 mRNA in various cell types and tissues by real-time reverse transcription-PCR. Clin Chem 47:2089–2097

    CAS  PubMed  Google Scholar 

  49. Vosper H, Patel L, Graham TL, Khoudoli GA, Hill A, Macphee CH, Pinto I, Smith SA, Suckling KE, Wolf CR, Palmer CNA (2001) The peroxisome proliferator-activated receptor δ promotes lipid accumulation in human macrophages. J Biol Chem 276:44258–44265

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

K.V.B. was supported by a Co-operative Award in Science and Engineering from the Biotechnology and Biological Research Council, sponsored by Glaxo SmithKline.

Author information

Authors and Affiliations

  1. Department of Veterinary Basic Sciences, Royal Veterinary College, Royal College St., London, NW1 0TU, UK

    Kelly V. Batt & Kathleen M. Botham

  2. Medicines Research Centre, GlaxoSmithKline, Gunnels Wood Rd., Stevenage, SG1 2NY, UK

    Lisa Patel & Keith E. Suckling

Authors
  1. Kelly V. Batt
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lisa Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kathleen M. Botham
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Keith E. Suckling
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kathleen M. Botham.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Batt, K.V., Patel, L., Botham, K.M. et al. Chylomicron remnants and oxidised low density lipoprotein have differential effects on the expression of mRNA for genes involved in human macrophage foam cell formation. J Mol Med 82, 449–458 (2004). https://doi.org/10.1007/s00109-004-0551-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-004-0551-2

Keywords

Search

Navigation