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Lipopolysaccharide represses the expression of ATP-binding cassette transporter G1 and scavenger receptor class B, type I in murine macrophages

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Abstract

Objective and design

To investigate the regulation of cholesterol transporters, including ATP-binding cassette transporter A1 (ABCA1), ABCG1 and scavenger receptor class B, type I (SR-BI), by inflammatory stimuli in macrophages.

Materials and treatments

RAW 264.7 macrophages and mouse peritoneal macrophages were treated with inflammatory stimuli with or without rosiglitazone, a peroxisome proliferator activated receptor γ (PPARγ) agonist, or T0901317, a liver X receptor (LXR) agonist.

Methods

Real-time PCR and Western blotting for cholesterol transporters as well as cellular cholesterol efflux to high-density lipoprotein 2 (HDL2) were determined.

Results

In RAW 264.7 macrophages, lipopolysaccharide (LPS) significantly reduced ABCG1 and PPARγ as well as cholesterol efflux to HDL2. Rosiglitazone and T0901317 induced ABCA1 and ABCG1 several-fold, but LPS reduced only ABCG1. ABCG1 and SR-BI proteins, but not ABCA1, were decreased by LPS. In mouse peritoneal macrophages, LPS, tumor necrosis factor α and interleukin-1β decreased ABCG1, SR-BI, LXRα and PPARγ mRNA. The agonists increased ABC transporter expression but LPS reduced mRNA of T0901317-induced ABCA1 as well as basal and agonists-induced ABCG1. SR-BI protein was increased by rosiglitazone but LPS decreased the levels.

Conclusion

The data suggest that inflammatory insults repress ABCG1 and SR-BI expression partly dependent on PPARγ with a minimal effect on ABCA1 expression.

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Abbreviations

ABCA1:

ATP-binding cassette transporter A1

ABCG1:

ATP-binding cassette transporter G1

HDL2 :

High-density lipoprotein 2

IL-1β:

Interleukin-1β

LFA-I:

Lipid-free apoA-I

LPS:

Lipopolysaccharide

LXR:

Liver X receptor

PGC-1:

PPARγ coactivator-1

PPARγ:

Peroxisome proliferator activated receptor γ

RCT:

Reverse cholesterol transport

RXR:

Retinoid X receptor

SR-BI:

Scavenger receptor class B, type I

TLR4:

Toll-like receptor 4

TNFα:

Tumor necrosis factor α

References

  1. Bensinger SJ, Tontonoz P. Integration of metabolism and inflammation by lipid-activated nuclear receptors. Nature. 2008;454:470–7.

    Article  PubMed  CAS  Google Scholar 

  2. Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest. 2006;116:1793–801.

    Article  PubMed  CAS  Google Scholar 

  3. Zelcer N, Tontonoz P. Liver X receptors as integrators of metabolic and inflammatory signaling. J Clin Invest. 2006;116:607–14.

    Article  PubMed  CAS  Google Scholar 

  4. Lusis AJ. Atherosclerosis. Nature. 2000;407:233–41.

    Article  PubMed  CAS  Google Scholar 

  5. Tall AR, Yvan-Charvet L, Terasaka N, Pagler T, Wang N. HDL, ABC transporters, and cholesterol efflux: implications for the treatment of atherosclerosis. Cell Metab. 2008;7:365–75.

    Article  PubMed  CAS  Google Scholar 

  6. van Reyk DM, Jessup W. The macrophage in atherosclerosis: modulation of cell function by sterols. J Leukoc Biol. 1999;66:557–61.

    PubMed  Google Scholar 

  7. Rigamonti E, Chinetti-Gbaguidi G, Staels B. Regulation of macrophage functions by PPAR-alpha, PPAR-gamma, and LXRs in mice and men. Arterioscler Thromb Vasc Biol. 2008;28:1050–9.

    Article  PubMed  CAS  Google Scholar 

  8. Moore KJ, Freeman MW. Scavenger receptors in atherosclerosis: beyond lipid uptake. Arterioscler Thromb Vasc Biol. 2006;26:1702–11.

    Article  PubMed  CAS  Google Scholar 

  9. Steinberg D. Atherogenesis in perspective: hypercholesterolemia and inflammation as partners in crime. Nat Med. 2002;8:1211–7.

    Article  PubMed  CAS  Google Scholar 

  10. Yancey PG, Bortnick AE, Kellner-Weibel G, Llera-Moya M, Phillips MC, Rothblat GH. Importance of different pathways of cellular cholesterol efflux. Arterioscler Thromb Vasc Biol. 2003;23:712–9.

    Article  PubMed  CAS  Google Scholar 

  11. Kennedy MA, Barrera GC, Nakamura K, Baldan A, Tarr P, Fishbein MC, et al. ABCG1 has a critical role in mediating cholesterol efflux to HDL and preventing cellular lipid accumulation. Cell Metab. 2005;1:121–31.

    Article  PubMed  CAS  Google Scholar 

  12. Wang Y, Kurdi-Haidar B, Oram JF. LXR-mediated activation of macrophage stearoyl-CoA desaturase generates unsaturated fatty acids that destabilize ABCA1. J Lipid Res. 2004;45:972–80.

    Article  PubMed  CAS  Google Scholar 

  13. Wang N, Lan D, Chen W, Matsuura F, Tall AR. ATP-binding cassette transporters G1 and G4 mediate cellular cholesterol efflux to high-density lipoproteins. Proc Natl Acad Sci USA. 2004;101:9774–9.

    Article  PubMed  CAS  Google Scholar 

  14. Ikonen E. Cellular cholesterol trafficking and compartmentalization. Nat Rev Mol Cell Biol. 2008;9:125–38.

    Article  PubMed  CAS  Google Scholar 

  15. Zhu X, Lee JY, Timmins JM, Brown JM, Boudyguina E, Mulya A, et al. Increased cellular free cholesterol in macrophage-specific Abca1 knock-out mice enhances pro-inflammatory response of macrophages. J Biol Chem. 2008;283:22930–41.

    Article  PubMed  CAS  Google Scholar 

  16. Yvan-Charvet L, Ranalletta M, Wang N, Han S, Terasaka N, Li R, et al. Combined deficiency of ABCA1 and ABCG1 promotes foam cell accumulation and accelerates atherosclerosis in mice. J Clin Invest. 2007;117:3900–8.

    PubMed  CAS  Google Scholar 

  17. Costet P, Luo Y, Wang N, Tall AR. Sterol-dependent transactivation of the ABC1 promoter by the liver X receptor/retinoid X receptor. J Biol Chem. 2000;275:28240–5.

    PubMed  CAS  Google Scholar 

  18. Li AC, Binder CJ, Gutierrez A, Brown KK, Plotkin CR, Pattison JW, et al. Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARalpha, beta/delta, and gamma. J Clin Invest. 2004;114:1564–76.

    PubMed  CAS  Google Scholar 

  19. Joseph SB, Bradley MN, Castrillo A, Bruhn KW, Mak PA, Pei L, et al. LXR-dependent gene expression is important for macrophage survival and the innate immune response. Cell. 2004;119:299–309.

    Article  PubMed  CAS  Google Scholar 

  20. Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature. 1998;391:79–82.

    Article  PubMed  CAS  Google Scholar 

  21. Khovidhunkit W, Moser AH, Shigenaga JK, Grunfeld C, Feingold KR. Endotoxin down-regulates ABCG5 and ABCG8 in mouse liver and ABCA1 and ABCG1 in J774 murine macrophages: differential role of LXR. J Lipid Res. 2003;44:1728–36.

    Article  PubMed  CAS  Google Scholar 

  22. Baranova I, Vishnyakova T, Bocharov A, Chen Z, Remaley AT, Stonik J, et al. Lipopolysaccharide down regulates both scavenger receptor B1 and ATP binding cassette transporter A1 in RAW cells. Infect Immun. 2002;70:2995–3003.

    Article  PubMed  CAS  Google Scholar 

  23. Park YK, Rasmussen HE, Ehler SJ, Blobaum KR, Lu F, Schlegel VL, et al. Repression of proinflammatory gene expression by lipid extract of Nostoc commune var sphaeroides Kutzing, a blue-green alga, via inhibition of nuclear factor-kappa B in RAW 264.7 macrophages. Nutr Res. 2008;28:83–92.

    Article  PubMed  CAS  Google Scholar 

  24. Rasmussen HE, Blobaum KR, Park YK, Ehlers SJ, Lu F, Lee JY. Lipid extract of Nostoc commune var. sphaeroides Kutzing, a blue-green alga, inhibits the activation of sterol regulatory element binding proteins in HepG2 cells. J Nutr. 2008;138:476–81.

    PubMed  CAS  Google Scholar 

  25. Lin YZ, Yao SY, Veach RA, Torgerson TR, Hawiger J. Inhibition of nuclear translocation of transcription factor NF-kappa B by a synthetic peptide containing a cell membrane-permeable motif and nuclear localization sequence. J Biol Chem. 1995;270:14255–8.

    Article  PubMed  CAS  Google Scholar 

  26. Weber C, Zernecke A, Libby P. The multifaceted contributions of leukocyte subsets to atherosclerosis: lessons from mouse models. Nat Rev Immunol. 2008;8:802–15.

    Article  PubMed  CAS  Google Scholar 

  27. Libby P. The molecular mechanisms of the thrombotic complications of atherosclerosis. J Intern Med. 2008;263:517–27.

    Article  PubMed  CAS  Google Scholar 

  28. Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med. 1999;340:115–26.

    Article  PubMed  CAS  Google Scholar 

  29. Danesh J, Collins R, Peto R. Chronic infections and coronary heart disease: is there a link? Lancet. 1997;350:430–6.

    Article  PubMed  CAS  Google Scholar 

  30. Gaydos CA, Summersgill JT, Sahney NN, Ramirez JA, Quinn TC. Replication of Chlamydia pneumoniae in vitro in human macrophages, endothelial cells, and aortic artery smooth muscle cells. Infect Immunol. 1996;64:1614–20.

    CAS  Google Scholar 

  31. Wiedermann CJ, Kiechl S, Dunzendorfer S, Schratzberger P, Egger G, Oberhollenzer F, et al. Association of endotoxemia with carotid atherosclerosis and cardiovascular disease: prospective results from the Bruneck Study. J Am Coll Cardiol. 1999; 34: 1975-1981.

    Google Scholar 

  32. Michelsen KS, Doherty TM, Shah PK, Arditi M. TLR signaling: an emerging bridge from innate immunity to atherogenesis. J Immunol. 2004;173:5901–7.

    PubMed  CAS  Google Scholar 

  33. Francone OL, Royer L, Boucher G, Haghpassand M, Freeman A, Brees D, et al. Increased cholesterol deposition, expression of scavenger receptors, and response to chemotactic factors in Abca1-deficient macrophages. Arterioscler Thromb Vasc Biol. 2005;25:1198–205.

    Article  PubMed  CAS  Google Scholar 

  34. Baldan A, Pei L, Lee R, Tarr P, Tangirala RK, Weinstein MM, et al. Impaired development of atherosclerosis in hyperlipidemic Ldlr−/− and ApoE−/− mice transplanted with Abcg1−/− bone marrow. Arterioscler Thromb Vasc Biol. 2006;26:2301–7.

    Article  PubMed  CAS  Google Scholar 

  35. Out R, Hoekstra M, Hildebrand RB, Kruit JK, Meurs I, Li Z, et al. Macrophage ABCG1 deletion disrupts lipid homeostasis in alveolar macrophages and moderately influences atherosclerotic lesion development in LDL receptor-deficient mice. Arterioscler Thromb Vasc Biol. 2006;26:2295–300.

    Article  PubMed  CAS  Google Scholar 

  36. Zhang W, Yancey PG, Su YR, Babaev VR, Zhang Y, Fazio S, et al. Inactivation of macrophage scavenger receptor class B type I promotes atherosclerotic lesion development in apolipoprotein E-deficient mice. Circulation. 2003;108:2258–63.

    Article  PubMed  CAS  Google Scholar 

  37. Van Eck M, Twisk J, Hoekstra M, Van Rij BT, Van der Lans CA, Bos IS, et al. Differential effects of scavenger receptor BI deficiency on lipid metabolism in cells of the arterial wall and in the liver. J Biol Chem. 2003;278:23699–705.

    Article  PubMed  Google Scholar 

  38. Adorni MP, Zimetti F, Billheimer JT, Wang N, Rader DJ, Phillips MC, et al. The roles of different pathways in the release of cholesterol from macrophages. J Lipid Res. 2007;48:2453–62.

    Article  PubMed  CAS  Google Scholar 

  39. Kaplan R, Gan X, Menke JG, Wright SD, Cai TQ. Bacterial lipopolysaccharide induces expression of ABCA1 but not ABCG1 via an LXR-independent pathway. J Lipid Res. 2002;43:952–9.

    PubMed  CAS  Google Scholar 

  40. Gerbod-Giannone MC, Li Y, Holleboom A, Han S, Hsu LC, Tabas I, et al. TNFalpha induces ABCA1 through NF-kappaB in macrophages and in phagocytes ingesting apoptotic cells. Proc Natl Acad Sci USA. 2006;103:3112–7.

    Article  PubMed  CAS  Google Scholar 

  41. Schmitz G, Langmann T. Transcriptional regulatory networks in lipid metabolism control ABCA1 expression. Biochim Biophys Acta. 2005;1735:1–19.

    PubMed  CAS  Google Scholar 

  42. Naik SU, Wang X, Da Silva JS, Jaye M, Macphee CH, Reilly MP, et al. Pharmacological activation of liver X receptors promotes reverse cholesterol transport in vivo. Circulation. 2006;113:90–7.

    Article  PubMed  CAS  Google Scholar 

  43. Chawla A, Boisvert WA, Lee CH, Laffitte BA, Barak Y, Joseph SB, et al. A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Mol Cell. 2001;7:161–71.

    Article  PubMed  CAS  Google Scholar 

  44. Chinetti G, Gbaguidi FG, Griglio S, Mallat Z, Antonucci M, Poulain P, et al. CLA-1/SR-BI Is expressed in atherosclerotic lesion macrophages and regulated by activators of peroxisome proliferator-activated receptors. Circulation. 2000;101:2411–7.

    PubMed  CAS  Google Scholar 

  45. Schoonjans K, Staels B, Auwerx J. The peroxisome proliferator activated receptors (PPARS) and their effects on lipid metabolism and adipocyte differentiation. Biochim Biophys Acta. 1996;1302:93–109.

    PubMed  CAS  Google Scholar 

  46. Jiang C, Ting AT, Seed B. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature. 1998;391:82–6.

    Article  PubMed  CAS  Google Scholar 

  47. Colville-Nash PR, Qureshi SS, Willis D, Willoughby DA. Inhibition of inducible nitric oxide synthase by peroxisome proliferator-activated receptor agonists: correlation with induction of heme oxygenase 1. J Immunol. 1998;161:978–84.

    PubMed  CAS  Google Scholar 

  48. Pascual G, Fong AL, Ogawa S, Gamliel A, Li AC, Perissi V, et al. A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma. Nature. 2005;437:759–63.

    Article  PubMed  CAS  Google Scholar 

  49. Kelly D, Campbell JI, King TP, Grant G, Jansson EA, Coutts AG, et al. Commensal anaerobic gut bacteria attenuate inflammation by regulating nuclear-cytoplasmic shuttling of PPAR-gamma and RelA. Nat Immunol. 2004;5:104–12.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

Research supported partly by Faculty Seed Grant from University of Nebraska-Lincoln Research Council and by funds from the College of Agriculture and Natural Resources, University of Connecticut, to J. Lee.

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  1. Department of Nutritional Sciences, University of Connecticut, Storrs, CT, 06269, USA

    Youngki Park, Tho X. Pham & Jiyoung Lee

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  1. Youngki Park
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Correspondence to Jiyoung Lee.

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Responsible Editor: Liwu Li.

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Park, Y., Pham, T.X. & Lee, J. Lipopolysaccharide represses the expression of ATP-binding cassette transporter G1 and scavenger receptor class B, type I in murine macrophages. Inflamm. Res. 61, 465–472 (2012). https://doi.org/10.1007/s00011-011-0433-3

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