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Phospholipase A2-Modified Low-Density Lipoprotein Activates Liver X Receptor in Human Macrophages

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Abstract

Macrophages respond to cholesterol accumulation by increasing cholesterol efflux, which is mediated by activation of the nuclear liver X receptor (LXR) and ATP binding cassette (ABC) transporters. In the present study, we investigated whether foam cell formation induced by phospholipase A2-modified low-density lipoprotein (PLA–LDL) influences LXR activity and cholesterol efflux in primary human monocyte-derived macrophages (MDMs). Macrophages were treated with PLA–LDL and expression of the LXR target genes ABCA1 and ABCG1 was analyzed by quantitative PCR and western blot. PLA–LDL time-dependently up-regulated ABCA1 and ABCG1 mRNA and protein. Removal of non-esterified fatty acids from PLA–LDL particles did not influence the induction of ABC transporters. A role of LXR in PLA–LDL-stimulated ABCG1 expression was verified by LXR-knockdown and luciferase reporter assays using a construct containing a LXR response element from the ABCG1 gene. Functionally, cholesterol efflux to apolipoprotein A-I and high-density lipoprotein was higher in PLA–LDL treated cells compared to controls. Together, these results demonstrate that in primary human MDMs PLA–LDL induces ABC transporter expression via LXR activation. A concomitantly increased cholesterol efflux may prevent excessive cholesterol accumulation and thus, attenuate foam cell formation.

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References

  1. Shibata, N., & Glass, C. K. (2009). Regulation of macrophage function in inflammation and atherosclerosis. Journal of Lipid Research, 50(Suppl), S277–S281.

    Article  PubMed  Google Scholar 

  2. Wooton-Kee, C. R., Boyanovsky, B. B., Nasser, M. S., de Villiers, W. J., & Webb, N. R. (2004). Group V sPLA2 hydrolysis of low-density lipoprotein results in spontaneous particle aggregation and promotes macrophage foam cell formation. Arteriosclerosis, Thrombosis, and Vascular Biology, 24, 762–767.

    Article  PubMed  CAS  Google Scholar 

  3. Oorni, K., Pentikainen, M. O., Ala-Korpela, M., & Kovanen, P. T. (2000). Aggregation, fusion, and vesicle formation of modified low density lipoprotein particles: Molecular mechanisms and effects on matrix interactions. Journal of Lipid Research, 41, 1703–1714.

    PubMed  CAS  Google Scholar 

  4. Boyanovsky, B. B., Shridas, P., Simons, M., van der Westhuyzen, D. R., & Webb, N. R. (2009). Syndecan-4 mediates macrophage uptake of group V secretory phospholipase A2-modified LDL. Journal of Lipid Research, 50, 641–650.

    Article  PubMed  CAS  Google Scholar 

  5. Namgaladze, D., & Brune, B. (2006). Phospholipase A2-modified low-density lipoprotein activates the phosphatidylinositol 3-kinase-Akt pathway and increases cell survival in monocytic cells. Arteriosclerosis, Thrombosis, and Vascular Biology, 26, 2510–2516.

    Article  PubMed  CAS  Google Scholar 

  6. Namgaladze, D., Morbitzer, D., von Knethen, A., & Brune, B. (2010). Phospholipase A2-modified low-density lipoprotein activates macrophage peroxisome proliferator-activated receptors. Arteriosclerosis, Thrombosis, and Vascular Biology, 30, 313–320.

    Article  PubMed  CAS  Google Scholar 

  7. Namgaladze, D., Preiss, S., Drose, S., Brandt, U., & Brune, B. (2010). Phospholipase A2-modified low density lipoprotein induces mitochondrial uncoupling and lowers reactive oxygen species in phagocytes. Atherosclerosis, 208, 142–147.

    Article  PubMed  CAS  Google Scholar 

  8. Tontonoz, P., & Mangelsdorf, D. J. (2003). Liver X receptor signaling pathways in cardiovascular disease. Molecular Endocrinology, 17, 985–993.

    Article  PubMed  CAS  Google Scholar 

  9. Repa, J. J., & Mangelsdorf, D. J. (2002). The liver X receptor gene team: Potential new players in atherosclerosis. Nature Medicine, 8, 1243–1248.

    Article  PubMed  CAS  Google Scholar 

  10. Lehmann, J. M., Kliewer, S. A., Moore, L. B., Smith-Oliver, T. A., Oliver, B. B., Su, J. L., et al. (1997). Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway. The Journal of biological chemistry, 272, 3137–3140.

    Article  PubMed  CAS  Google Scholar 

  11. Tangirala, R. K., Bischoff, E. D., Joseph, S. B., Wagner, B. L., Walczak, R., Laffitte, B. A., et al. (2002). Identification of macrophage liver X receptors as inhibitors of atherosclerosis. Proceedings of the National academy of Sciences of the United States of America, 99, 11896–11901.

    Article  PubMed  CAS  Google Scholar 

  12. Joseph, S. B., McKilligin, E., Pei, L., Watson, M. A., Collins, A. R., Laffitte, B. A., et al. (2002). Synthetic LXR ligand inhibits the development of atherosclerosis in mice. Proceedings of the National academy of Sciences of the United States of America, 99, 7604–7609.

    Article  PubMed  CAS  Google Scholar 

  13. Ghisletti, S., Huang, W., Ogawa, S., Pascual, G., Lin, M. E., Willson, T. M., et al. (2007). Parallel SUMOylation-dependent pathways mediate gene and signal-specific transrepression by LXRs and PPAR gamma. Molecular Cell, 25, 57–70.

    Article  PubMed  CAS  Google Scholar 

  14. Chawla, A., Boisvert, W. A., Lee, C. H., Laffitte, B. A., Barak, Y., Joseph, S. B., et al. (2001). A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Molecular Cell, 7, 161–171.

    Article  PubMed  CAS  Google Scholar 

  15. Sabol, S. L., Brewer, H. B., Jr, & Santamarina-Fojo, S. (2005). The human ABCG1 gene: Identification of LXR response elements that modulate expression in macrophages and liver. Journal of Lipid Research, 46, 2151–2167.

    Article  PubMed  CAS  Google Scholar 

  16. Parthasarathy, S., Printz, D. J., Boyd, D., Joy, L., & Steinberg, D. (1986). Macrophage oxidation of low density lipoprotein generates a modified form recognized by the scavenger receptor. Arteriosclerosis, 6, 505–510.

    Article  PubMed  CAS  Google Scholar 

  17. Zhao, B., Li, Y., Buono, C., Waldo, S. W., Jones, N. L., Mori, M., et al. (2006). Constitutive receptor-independent low density lipoprotein uptake and cholesterol accumulation by macrophages differentiated from human monocytes with macrophage-colony-stimulating factor (M-CSF). Journal of Biological Chemistry, 281, 15757–15762.

    Article  PubMed  CAS  Google Scholar 

  18. Fu, X., Menke, J. G., Chen, Y., Zhou, G., MacNaul, K. L., Wright, S. D., et al. (2001). 27-Hydroxycholesterol is an endogenous ligand for liver X receptor in cholesterol-loaded cells. Journal of Biological Chemistry, 276, 38378–38387.

    Article  PubMed  CAS  Google Scholar 

  19. Uehara, Y., Miura, S., von Eckardstein, A., Abe, S., Fujii, A., Matsuo, Y., et al. (2007). Unsaturated fatty acids suppress the expression of the ATP-binding cassette transporter G1 (ABCG1) and ABCA1 genes via an LXR/RXR responsive element. Atherosclerosis, 191, 11–21.

    Article  PubMed  CAS  Google Scholar 

  20. Wang, Y., & Oram, J. F. (2007). Unsaturated fatty acids phosphorylate and destabilize ABCA1 through a protein kinase C delta pathway. Journal of Lipid Research, 48, 1062–1068.

    Article  PubMed  CAS  Google Scholar 

  21. Wang, N., Lan, D., Chen, W., Matsuura, F., & Tall, A. R. (2004). ATP-binding cassette transporters G1 and G4 mediate cellular cholesterol efflux to high-density lipoproteins. Proceedings of the National academy of Sciences of the United States of America, 101, 9774–9779.

    Article  PubMed  CAS  Google Scholar 

  22. Larrede, S., Quinn, C. M., Jessup, W., Frisdal, E., Olivier, M., Hsieh, V., et al. (2009). Stimulation of cholesterol efflux by LXR agonists in cholesterol-loaded human macrophages is ABCA1-dependent but ABCG1-independent. Arteriosclerosis, Thrombosis, and Vascular Biology, 29, 1930–1936.

    Article  PubMed  CAS  Google Scholar 

  23. Terasaka, N., Wang, N., Yvan-Charvet, L., & Tall, A. R. (2007). High-density lipoprotein protects macrophages from oxidized low-density lipoprotein-induced apoptosis by promoting efflux of 7-ketocholesterol via ABCG1. Proceedings of the National academy of Sciences of the United States of America, 104, 15093–15098.

    Article  PubMed  CAS  Google Scholar 

  24. Seres, L., Cserepes, J., Elkind, N. B., Torocsik, D., Nagy, L., Sarkadi, B., et al. (2008). Functional ABCG1 expression induces apoptosis in macrophages and other cell types. Biochimica et Biophysica Acta, 1778, 2378–2387.

    Article  PubMed  CAS  Google Scholar 

  25. Chinetti-Gbaguidi, G., & Staels, B. (2011). Macrophage polarization in metabolic disorders: Functions and regulation. Current Opinion in Lipidology, 22, 365–372.

    Article  PubMed  CAS  Google Scholar 

  26. Fontaine, C., Rigamonti, E., Nohara, A., Gervois, P., Teissier, E., Fruchart, J. C., et al. (2007). Liver X receptor activation potentiates the lipopolysaccharide response in human macrophages. Circulation Research, 101, 40–49.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was supported by grants from the Deutsche Forschungsgemeinschaft (Br999) and Translational Research Innovation-Pharma (TRIP). We thanked Steven L. Sabol (National Institutes of Health, Bethesda/USA) for providing the LXRE reporter constructs and Franz-Joseph Streb for technical assistance.

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Authors and Affiliations

  1. Faculty of Medicine, Institute of Biochemistry I/ZAFES, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany

    Daniel Morbitzer, Dmitry Namgaladze & Bernhard Brüne

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  1. Daniel Morbitzer
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  2. Dmitry Namgaladze
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  3. Bernhard Brüne
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Correspondence to Bernhard Brüne.

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Daniel Morbitzer and Dmitry Namgaladze contributed equally to this work.

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Morbitzer, D., Namgaladze, D. & Brüne, B. Phospholipase A2-Modified Low-Density Lipoprotein Activates Liver X Receptor in Human Macrophages. Cell Biochem Biophys 63, 143–149 (2012). https://doi.org/10.1007/s12013-012-9351-4

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