Skip to main content
SpringerLink
Log in

NO-1886 Up-regulates Niemann–Pick C1 Protein (NPC1) Expression Through Liver X Receptor α Signaling Pathway in THP-1 Macrophage-Derived Foam Cells

  • Published:
Cardiovascular Drugs and Therapy Aims and scope Submit manuscript

Abstract

Background

The Niemann–Pick C1 (NPC1) protein regulates the transport of cholesterol from late endosomes/lysosomes to other compartments responsible for maintaining intracellular cholesterol homeostasis. Liver X receptors (LXRs) operate as cholesterol sensors which may protect from cholesterol overload by increasing the amount of free cholesterol in the plasma membrane through inducing NPC1 expression. NO-1886 has been proven to be highly effective at increasing liver X receptor α expression and promoting cellular cholesterol efflux. In this study, the effects of NO-1886 on NPC1 expression were investigated in THP-1 macrophage-derived foam cells.

Methods and results

Results showed that NO-1886 markedly increased expression of NPC1 at both mRNA level and protein level in a dose-dependent and time-dependent manner. Cellular cholesterol content was decreased while cholesterol efflux was increased by NO-1886 treatment. In addition, LXR α was also up-regulated by NO-1886 treatment. And LXR α small interfering RNA completely abolished the promotion effect which was induced by NO-1886.

Conclusion

These results provide evidence that NO-1886 up-regulates expression of NPC1 through LXR α pathway in THP-1 macrophage- derived foam cells.

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

Similar content being viewed by others

Abbreviations

NPC1:

Niemann–Pick C1

ABCA1:

ATP-binding cassette transporter A1

LXR α :

liver X receptor α

RCT:

reverse cholesterol transport

HDL:

high density lipoprotein

LPL:

lipoprotein lipase

References

  1. Rubins HB, Robins SJ, Iwane MK, et al. Rationale and design of the Department of Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (HIT) for secondary prevention of coronary artery disease in men with low high-density lipoprotein cholesterol and desirable low-density lipoprotein cholesterol. Am J Cardiol. 1993;71:45–52.

    Article  PubMed  CAS  Google Scholar 

  2. Yokoyama S. Release of cellular cholesterol: molecular mechanism for cholesterol homeostasis in cells and in the body. Biochim Biophys Acta. 2000;1529:231–44.

    PubMed  CAS  Google Scholar 

  3. Oram JF, Heinecke JW. ATP-binding cassette transporter A1: a cell cholesterol exporter that protects against cardiovascular disease. Physiol Rev. 2005;85:1343–72.

    Article  PubMed  CAS  Google Scholar 

  4. Vanier MT. Biochemical studies in Niemann–Pick disease. I. Major sphingolipids of liver and spleen. Biochim Biophys Acta. 1983;750:178–84.

    PubMed  CAS  Google Scholar 

  5. Blanchette-Mackie EJ, Dwyer NK, Amende LM, et al. Type-C Niemann–Pick disease: low density lipoprotein uptake is associated with premature cholesterol accumulation in the Golgi complex and excessive cholesterol storage in lysosomes. Proc Natl Acad Sci USA. 1988;85:8022–6.

    Article  PubMed  CAS  Google Scholar 

  6. Goldin E, Roff CF, Miller SP, et al. Type C Niemann–Pick disease: a murine model of the lysosomal cholesterol lipidosis accumulates sphingosine and sphinganine in liver. Biochim Biophys Acta. 1992;1127:303–11.

    PubMed  CAS  Google Scholar 

  7. Zervas M, Somers KL, Thrall MA, et al. Critical role for glycosphingolipids in Niemann–Pick disease type C. Curr Biol. 2001;11:1283–7.

    Article  PubMed  CAS  Google Scholar 

  8. Ory DS. Nuclear receptor signaling in the control of cholesterol homeostasis: have the orphans found a home? Circ Res. 2004;95:660–70.

    Article  PubMed  CAS  Google Scholar 

  9. Chawla A, Repa JJ, Evans RM, et al. Nuclear receptors and lipid physiology: opening the X-files. Science 2001;294:1866–70.

    Article  PubMed  CAS  Google Scholar 

  10. Zhang JR, Coleman T, Langmade SJ, et al. Niemann–Pick C1 protects against atherosclerosis in mice via regulation of macrophage intracellular cholesterol trafficking. J Clin Invest. 2008;118:2281–90.

    PubMed  CAS  Google Scholar 

  11. Dai XY, Ou X, Hao XR, et al. The effect of T0901317 on ATP-binding cassette transporter A1 and Niemann–Pick type C1 in apoE−/− mice. J Cardiovasc Pharmacol. 2008;51:467–75.

    Article  PubMed  CAS  Google Scholar 

  12. Ou X, Dai XY, Long ZF, et al. Liver X receptor agonist T0901317 reduces atherosclerotic atherosclerotic lesions in apoE−/− mice by up-regulating NPC1 expression. Sci China Ser C-Life Sci. 2008;51:418–29.

    Article  CAS  Google Scholar 

  13. Tsutsumi K, Inoue Y, Shima A, et al. The novel compound NO-1886 increases lipoprotein lipase activity with resulting elevation of high density lipoprotein cholesterol, and long-term administration inhibits atherogenesis in the coronary arteries of rats with experimental atherosclerosis. J Clin Invest. 1993;92:411–7.

    Article  PubMed  CAS  Google Scholar 

  14. Zhang C, Yin W, Liao D, et al. NO-1886 upregulates ATP binding cassette transporter A1 and inhibits diet-induced atherosclerosis in Chinese Bama minipigs. J Lipid Res. 2006;47:2055–63.

    Article  PubMed  CAS  Google Scholar 

  15. Ayaori M, Sawada S, Yonemura A, et al. Glucocorticoid receptor regulates ATP-binding cassette transporter-A1 expression and apolipoprotein-mediated cholesterol efflux from macrophages. Arterioscler Thromb Vasc Biol. 2006;26:163–8.

    Article  PubMed  CAS  Google Scholar 

  16. Tang C, Wang Z, Yi G, et al. Effect of rolipram on ATP binding cassette transporter 1 and Cholesterol efflux in THP-1 macrophage-derived foam cell. Chin Pharmacol Bull. 2003;19:1177–82.

    CAS  Google Scholar 

  17. Wang N, Silver DL, Thiele C, et al. ATP-binding cassette transporter A1 (ABCA1) functions as a cholesterol efflux regulatory protein. J Biol Chem. 2001;276:23742–7.

    Article  PubMed  CAS  Google Scholar 

  18. Scott C, Ioannou YA. The NPC1 protein: structure implies function. Biochim Biophys Acta. 2004;1685:8–13.

    PubMed  CAS  Google Scholar 

  19. Rigamonti E, Helin L, Lestavel S, et al. Liver X receptor activation controls intracellular cholesterol trafficking and esterification in human macrophages. Circ Res. 2005;97:682–9.

    Article  PubMed  CAS  Google Scholar 

  20. Tabas I. Cholesterol and phospholipid metabolism in macrophages. Biochim Biophys Acta. 2000;1529:164–74.

    PubMed  CAS  Google Scholar 

  21. Garver WS, Heidenreich RA. The Niemann–Pick C proteins and trafficking of cholesterol through the late endosomal/lysosomal system. Curr Mol Med. 2002;2:485–505.

    Article  PubMed  CAS  Google Scholar 

  22. Watari H, Blanchette-Mackie EJ, Dwyer NK, et al. Niemann–Pick C1 protein: obligatory roles for N-terminal domains and lysosomal targeting in cholesterol mobilization. Proc Natl Acad Sci USA. 1999;96:805–10.

    Article  PubMed  CAS  Google Scholar 

  23. Chen W, Sun Y, Welch C, et al. Preferential ATP-binding cassette transporter A1-mediated cholesterol efflux from late endosomes/lysosomes. J Biol Chem. 2001;276:43564–9.

    Article  PubMed  CAS  Google Scholar 

  24. Kusunoki M, Tsutsmi K, Inoue Y, et al. lipoprotein lipase activator NO-1886. Metabolism 2004;53:260–3.

    Article  PubMed  CAS  Google Scholar 

  25. Kusunoki M, Hara T, Tsutsmi K, et al. lipoprotein lipase activator NO-1886. Diabetologia 2000;43:875–80.

    Article  PubMed  CAS  Google Scholar 

  26. Yin W, Liao D, Kusunoki M, et al. NO-1886 decreases ectopic lipid deposition and protects pancreatic beta cells in diet-induced diabetic swine. J Endocrinol. 2004;180:399–408.

    Article  PubMed  CAS  Google Scholar 

  27. Yin W, Liao D, Wang Z, et al. NO-1886 inhibits size of adipocytes, suppresses plasma levels of tumor necrosis factor-alpha and free fatty acids, improves glucose metabolism in high-fat/high sucrose-fed miniature pigs. Pharmacol Res. 2004;49:199–206.

    Article  PubMed  CAS  Google Scholar 

  28. Scott C, Higgins ME, Davies JP, et al. Targeting of NPC1 to late endosomes involves multiple signals, including one residing within the putative sterol-sensing domain. J Biol Chem. 2004;279:48214–23.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

The authors gratefully acknowledge the financial support from the National Natural Sciences Foundation of China (30470720), Post-doctor Sciences Foundation of China (2005037157), Hunan Provincial Natural Sciences Foundation of China (06jj5058) and The National Major Basic Research Program of China (973 Program) (grant no. 2006CB503808).

Author information

Authors and Affiliations

  1. Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Life Science Research Center, University of South China, Hengyang, Hunan, 421001, China

    Xin Ma, Yan-Wei Hu, Zhong-Cheng Mo, Xiao-Xu Li, Xie-Hong Liu, Ji Xiao, Wei-Dong Yin & Chao-Ke Tang

  2. Department of Anesthesiology, The First Affiliated Hospital of University of South China, Hengyang, Hunan, 421001, China

    Xin Ma

  3. Institute of Pharmacy and Pharmacology, Life Science Research Center, University of South China, Hengyang, Hunan, 421001, China

    Duan-Fang Liao

Authors
  1. Xin Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yan-Wei Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhong-Cheng Mo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiao-Xu Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xie-Hong Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ji Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wei-Dong Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Duan-Fang Liao
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Chao-Ke Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chao-Ke Tang.

Additional information

Xin Ma and Yan-Wei Hu contributed equally to this study.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ma, X., Hu, YW., Mo, ZC. et al. NO-1886 Up-regulates Niemann–Pick C1 Protein (NPC1) Expression Through Liver X Receptor α Signaling Pathway in THP-1 Macrophage-Derived Foam Cells. Cardiovasc Drugs Ther 23, 199–206 (2009). https://doi.org/10.1007/s10557-009-6165-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10557-009-6165-8

Key words

Search

Navigation