Skip to main content
SpringerLink
Log in

Trimethylamine-N-Oxide Treatment Induces Changes in the ATP-Binding Cassette Transporter A1 and Scavenger Receptor A1 in Murine Macrophage J774A.1 cells

  • Original Article
  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Background: Recently, trimethylamine N-oxide was introduced as a risk factor for atherosclerosis in terms of helping foam cell formation and worsening atherosclerosis complications. The present study was performed to investigate whether/how trimethylamine N-oxide is involved in regulation of ATP-binding cassette transporter A1 and scavenger receptor A1 in macrophages at both mRNA and protein levels. Methods: Murine macrophage J774A.1 cells were treated with micromolar concentrations of trimethylamine N-oxide and 4-phenylbutyric acid, a chemical chaperon, for different time intervals. Tunicamycin was also used as a control for induction of endoplasmic reticulum stress. Results: Similar to tunicamycin, trimethylamine N-oxide increased scavenger receptor A1 in all treatment periods, whereas ATP-binding cassette transporter A1 was only reduced 24 h post-treatment with trimethylamine N-oxide at both mRNA and protein levels. In contrast, 4-phenylbutyric acid failed to induce such changes in either scavenger receptor A1 or ATP-binding cassette transporter A1. Conclusions: The results of this study, in agreement with previous studies, confirm the mechanistic role of trimethylamine N-oxide in the upregulation of scavenger receptor A1, which potentially can promote its proatherogenic role. The results also showed downregulation of ATP-binding cassette transporter A1 in trimethylamine N-oxide treated macrophages which may indicate another possible proatherosclerotic mechanism for foam cell formation.

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
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Wang, Z., E. Klipfell, B.J. Bennett, R. Koeth, B.S. Levison, B. Dugar, A.E. Feldstein, E.B. Britt, X. Fu, Y.M. Chung, et al. 2011. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472: 57–63.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Koeth, R.A., Z. Wang, B.S. Levison, J.A. Buffa, E. Org, B.T. Sheehy, E.B. Britt, X. Fu, Y. Wu, L. Li, et al. 2013. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 19: 576–585.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Hatori, K., T. Iwasaki, and R. Wada. 2014. Effect of urea and trimethylamine N-oxide on the binding between actin molecules. Biophys Chem 193–194: 20–26.

    Article  PubMed  Google Scholar 

  4. Canchi, D.R., P. Jayasimha, D.C. Rau, G.I. Makhatadze, and A.E. Garcia. 2012. Molecular mechanism for the preferential exclusion of TMAO from protein surfaces. J Phys Chem B 116: 12095–12104.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Yancey, P.H., M.E. Clark, S.C. Hand, R.D. Bowlus, and G.N. Somero. 1982. Living with water stress: evolution of osmolyte systems. Science 217: 1214–1222.

    Article  CAS  PubMed  Google Scholar 

  6. Lenky, C.C., C.J. McEntyre, and M. Lever. 2012. Measurement of marine osmolytes in mammalian serum by liquid chromatography-tandem mass spectrometry. Anal Biochem 420: 7–12.

    Article  CAS  PubMed  Google Scholar 

  7. Treberg, J.R., C.E. Wilson, R.C. Richards, K.V. Ewart, and W.R. Driedzic. 2002. The freeze-avoidance response of smelt Osmerus mordax: initiation and subsequent suppression of glycerol, trimethylamine oxide and urea accumulation. J Exp Biol 205: 1419–1427.

    CAS  PubMed  Google Scholar 

  8. Cho, S.S., G. Reddy, J.E. Straub, and D. Thirumalai. 2011. Entropic stabilization of proteins by TMAO. J Phys Chem B 115: 13401–13407.

    Article  CAS  PubMed  Google Scholar 

  9. Hunger, J., K.J. Tielrooij, R. Buchner, M. Bonn, and H.J. Bakker. 2012. Complex formation in aqueous trimethylamine-N-oxide (TMAO) solutions. J Phys Chem B 116: 4783–4795.

    Article  CAS  PubMed  Google Scholar 

  10. Lin, T.Y., and S.N. Timasheff. 1994. Why do some organisms use a urea-methylamine mixture as osmolyte? Thermodynamic compensation of urea and trimethylamine N-oxide interactions with protein. Biochemistry 33: 12695–12701.

    Article  CAS  PubMed  Google Scholar 

  11. Serkova, N., T.F. Fuller, J. Klawitter, C.E. Freise, and C.U. Niemann. 2005. H-NMR-based metabolic signatures of mild and severe ischemia/reperfusion injury in rat kidney transplants. Kidney Int 67: 1142–1151.

    Article  CAS  PubMed  Google Scholar 

  12. Bain, M.A., R. Faull, G. Fornasini, R.W. Milne, and A.M. Evans. 2006. Accumulation of trimethylamine and trimethylamine-N-oxide in end-stage renal disease patients undergoing haemodialysis. Nephrol Dial Transplant 21: 1300–1304.

    Article  CAS  PubMed  Google Scholar 

  13. Fujiwara, M., K. Arifuku, I. Ando, and T. Nemoto. 2005. Pattern recognition analysis for classification of hypertensive model rats and diurnal variation using 1H-NMR spectroscopy of urine. Anal Sci 21: 1259–1262.

    Article  CAS  PubMed  Google Scholar 

  14. Strom, A.R., J.A. Olafsen, and H. Larsen. 1979. Trimethylamine oxide: a terminal electron acceptor in anaerobic respiration of bacteria. J Gen Microbiol 112: 315–320.

    Article  CAS  PubMed  Google Scholar 

  15. Murphy, J.E., P.R. Tedbury, S. Homer-Vanniasinkam, J.H. Walker, and S. Ponnambalam. 2005. Biochemistry and cell biology of mammalian scavenger receptors. Atherosclerosis 182: 1–15.

    Article  CAS  PubMed  Google Scholar 

  16. Plüddemann, A., C. Neyen, and S. Gordon. 2007. Macrophage scavenger receptors and host-derived ligands. Methods 43: 207–217.

    Article  PubMed  Google Scholar 

  17. Tang, C., and J.F. Oram. 1791. The cell cholesterol exporter ABCA1 as a protector from cardiovascular disease and diabetes. Biochim Biophys Acta 2009: 563–572.

    Google Scholar 

  18. Tall, A.R., P. Costet, and N. Wang. 2002. Regulation and mechanisms of macrophage cholesterol efflux. J Clin Invest 110: 899–904.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Wellington, C.L., E.K. Walker, A. Suarez, A. Kwok, N. Bissada, R. Singaraja, Y.Z. Yang, L.H. Zhang, E. James, J.E. Wilson, et al. 2002. ABCA1 mRNA and protein distribution patterns predict multiple different roles and levels of regulation. Lab Invest 82: 273–283.

    Article  CAS  PubMed  Google Scholar 

  20. Loscalzo, J. 2011. Lipid metabolism by gut microbes and atherosclerosis. Circ Res 109: 127–129.

    Article  CAS  PubMed  Google Scholar 

  21. Ruijter, J.M., C. Ramakers, W.M. Hoogaars, Y. Karlen, O. Bakker, M.J. van den Hoff, and A.F. Moorman. 2009. Amplification efficiency: linking baseline and bias in the analysis of quantitative PCR data. Nucleic Acids Res 37, e45.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Street, T.O., K.A. Krukenberg, J. Rosgen, D.W. Bolen, and D.A. Agard. 2010. Osmolyte-induced conformational changes in the Hsp90 molecular chaperone. Protein Sci 19: 57–65.

    PubMed Central  CAS  PubMed  Google Scholar 

  23. Gong, B., L.Y. Zhang, C.P. Pang, D.S. Lam, and G.H. Yam. 2009. Trimethylamine N-oxide alleviates the severe aggregation and ER stress caused by G98R alphaA-crystallin. Mol Vis 15: 2829–2840.

    PubMed Central  CAS  PubMed  Google Scholar 

  24. Bennett, B.J., T.Q. de Aguiar Vallim, Z. Wang, D.M. Shih, Y. Meng, J. Gregory, H. Allayee, R. Lee, M. Graham, R. Crooke, et al. 2013. Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metab 17: 49–60.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Brown, J.M., and S.L. Hazen. 2014. Metaorganismal nutrient metabolism as a basis of cardiovascular disease. Curr Opin Lipidol 25: 48–53.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Macdonald, R.D., and M. Khajehpour. 2013. Effects of the osmolyte TMAO (Trimethylamine-N-oxide) on aqueous hydrophobic contact-pair interactions. Biophys Chem 184: 101–107.

    Article  CAS  PubMed  Google Scholar 

  27. Suzuki, S., A. Kubo, H. Shinano, and K. Takama. 1992. Inhibition of the electron transport system in Staphylococcus aureus by trimethylamine-N-oxide. Microbios 71: 145–148.

    CAS  PubMed  Google Scholar 

  28. Malhotra, J.D., and R.J. Kaufman. 2007. The endoplasmic reticulum and the unfolded protein response. Semin Cell Dev Biol 18: 716–731.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Schroder, M., and R.J. Kaufman. 2005. ER stress and the unfolded protein response. Mutat Res 569: 29–63.

    Article  PubMed  Google Scholar 

  30. Shen, X., K. Zhang, and R.J. Kaufman. 2004. The unfolded protein response--a stress signaling pathway of the endoplasmic reticulum. J Chem Neuroanat 28: 79–92.

    Article  CAS  PubMed  Google Scholar 

  31. Kennedy, D., A. Samali, and R. Jager. 2015. Methods for Studying ER Stress and UPR Markers in Human Cells. Methods Mol Biol 1292: 3–18.

    Article  PubMed  Google Scholar 

  32. Samali, A., U. Fitzgerald, S. Deegan, and S. Gupta. 2010. Methods for monitoring endoplasmic reticulum stress and the unfolded protein response. Int J Cell Biol 2010: 830307.

    PubMed Central  PubMed  Google Scholar 

  33. Wiley, J.C., J.S. Meabon, H. Frankowski, E.A. Smith, L.C. Schecterson, M. Bothwell, and W.C. Ladiges. 2010. Phenylbutyric acid rescues endoplasmic reticulum stress-induced suppression of APP proteolysis and prevents apoptosis in neuronal cells. PLoS One 5, e9135.

    Article  PubMed Central  PubMed  Google Scholar 

  34. Castilho, G., L.S. Okuda, R.S. Pinto, R.T. Iborra, E.R. Nakandakare, C.X. Santos, F.R. Laurindo, and M. Passarelli. 2012. ER stress is associated with reduced ABCA-1 protein levels in macrophages treated with advanced glycated albumin - reversal by a chemical chaperone. Int J Biochem Cell Biol 44: 1078–1086.

    Article  CAS  PubMed  Google Scholar 

  35. de Souza, Pinto R., G. Castilho, B.A. Paim, A. Machado-Lima, N.M. Inada, E.R. Nakandakare, A.E. Vercesi, and M. Passarelli. 2012. Inhibition of macrophage oxidative stress prevents the reduction of ABCA-1 transporter induced by advanced glycated albumin. Lipids 47: 443–450.

    Article  Google Scholar 

  36. Zani, I.A., S.L. Stephen, N.A. Mughal, D. Russell, S. Homer-Vanniasinkam, S.B. Wheatcroft, and S. Ponnambalam. 2015. Scavenger receptor structure and function in health and disease. Cells 4: 178–201.

    Article  PubMed Central  PubMed  Google Scholar 

  37. Kzhyshkowska, J., C. Neyen, and S. Gordon. 2012. Role of macrophage scavenger receptors in atherosclerosis. Immunobiology 217: 492–502.

    Article  CAS  PubMed  Google Scholar 

  38. Yao, S., C. Miao, H. Tian, H. Sang, N. Yang, P. Jiao, J. Han, C. Zong, and S. Qin. 2014. Endoplasmic reticulum stress promotes macrophage-derived foam cell formation by up-regulating cluster of differentiation 36 (CD36) expression. J Biol Chem 289: 4032–4042.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Yao, S.T., L. Zhao, C. Miao, H. Tian, N.N. Yang, S.D. Guo, L. Zhai, J. Chen, Y.W. Wang, and S.C. Qin. 2014. [Endoplasmic reticulum stress mediates oxidized low density lipoprotein-induced scavenger receptor A1 upregulation in macrophages]. Sheng Li Xue Bao 66: 612–618.

    CAS  PubMed  Google Scholar 

  40. Hotamisligil, G.S. 2010. Endoplasmic reticulum stress and atherosclerosis. Nat Med 16: 396–399.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Myoishi, M., H. Hao, T. Minamino, K. Watanabe, K. Nishihira, K. Hatakeyama, Y. Asada, K. Okada, H. Ishibashi-Ueda, G. Gabbiani, et al. 2007. Increased endoplasmic reticulum stress in atherosclerotic plaques associated with acute coronary syndrome. Circulation 116: 1226–1233.

    Article  PubMed  Google Scholar 

  42. Zhou, J., S. Lhotak, B.A. Hilditch, and R.C. Austin. 2005. Activation of the unfolded protein response occurs at all stages of atherosclerotic lesion development in apolipoprotein E-deficient mice. Circulation 111: 1814–1821.

    Article  CAS  PubMed  Google Scholar 

  43. Feng, B., P.M. Yao, Y. Li, C.M. Devlin, D. Zhang, H.P. Harding, M. Sweeney, J.X. Rong, G. Kuriakose, E.A. Fisher, et al. 2003. The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages. Nat Cell Biol 5: 781–792.

    Article  CAS  PubMed  Google Scholar 

  44. Pineau, L., J. Colas, S. Dupont, L. Beney, P. Fleurat-Lessard, J.M. Berjeaud, T. Berges, and T. Ferreira. 2009. Lipid-induced ER stress: synergistic effects of sterols and saturated fatty acids. Traffic 10: 673–690.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported financially by vice chancellor in research of Kerman University of Medical Sciences. We also thank the heads of the Department of Physiology and the Leishmaniasis Research Center of Afzalipour School of Medicine, Kerman University of Medical Sciences for their valuable assistance.

Financial Support

This study is funded by vice chancellor in research of Kerman University of Medical Sciences.

Conflict of Interest

The authors have no conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Clinical Biochemistry, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman, Iran

    Abbas Mohammadi, Ahmad Gholamhoseynian Najar & Zakaria Vahabzadeh

  2. Endocrine and Metabolism Research Center, Institute of Basic and Clinical Physiology, Kerman University of Medical Sciences, Kerman, Iran

    Abbas Mohammadi

  3. Research Department of Biotechnology, Institute of Sciences and High Technology and Environmental Sciences, Graduate University of Advanced Technology, Kerman, Iran

    Mohammad Mehdi Yaghoobi

  4. Social Determinants of Health Research Center, Institute of Futures Studies in Health, Department of Biostatistics and Epidemiology, School of Public Health, Kerman University of Medical Sciences, Kerman, Iran

    Yunes Jahani

Authors
  1. Abbas Mohammadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ahmad Gholamhoseynian Najar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mohammad Mehdi Yaghoobi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yunes Jahani
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zakaria Vahabzadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zakaria Vahabzadeh.

Additional information

Authors’ Contributions

Abbas Mohammadi carried out the design and supervised the study, and participated in manuscript preparation. Ahmad Gholamhoseynian Najar provided assistance in the design of the study, coordinated in manuscript preparation. Mohammad Mehdi Yaghoobi provided assistance in the design of primers and real time PCR experiments and participated in manuscript preparation. Yunes Jahani assisted in the statistical analysis of the study. Zakaria Vahabzadeh carried out all the experiments and prepared the manuscript. All authors have read and approved the content of the manuscript.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mohammadi, A., Najar, A.G., Yaghoobi, M.M. et al. Trimethylamine-N-Oxide Treatment Induces Changes in the ATP-Binding Cassette Transporter A1 and Scavenger Receptor A1 in Murine Macrophage J774A.1 cells. Inflammation 39, 393–404 (2016). https://doi.org/10.1007/s10753-015-0261-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-015-0261-7

KEY WORDS

Search

Navigation