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The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.

The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1)

Garcia-Calvo, Margarita, Lisnock, JeanMarie, Bull, Herbert G., Hawes, Brian E., Burnett, Duane A., Braun, Matthew P., Crona, James H., Davis, Harry R., Dean, Dennis C., Detmers, Patricia A., Graziano, Michael P., Hughes, Meredith, MacIntyre, D. Euan, Ogawa, Anthony, O'Neill, Kim A., Iyer, Sai Prasad N., Shevell, Diane E., Smith, Marsha M., Tang, Yui S., Makarewicz, Amanda M., Ujjainwalla, Feroze, Altmann, Scott W., Chapman, Kevin T., Thornberry, Nancy A.·2005·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0500269102
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Abstract

Ezetimibe is a potent inhibitor of cholesterol absorption that has been approved for the treatment of hypercholesterolemia, but its molecular target has been elusive. Using a genetic approach, we recently identified Niemann-Pick C1-Like 1 (NPC1L1) as a critical mediator of cholesterol absorption and an essential component of the ezetimibe-sensitive pathway. To determine whether NPC1L1 is the direct molecular target of ezetimibe, we have developed a binding assay and shown that labeled ezetimibe glucuronide binds specifically to a single site in brush border membranes and to human embryonic kidney 293 cells expressing NPC1L1. Moreover, the binding affinities of ezetimibe and several key analogs to recombinant NPC1L1 are virtually identical to those observed for native enterocyte membranes. K D values of ezetimibe glucuronide for mouse, rat, rhesus monkey, and human NPC1L1 are 12,000, 540, 40, and 220 nM, respectively. Last, ezetimibe no longer binds to membranes from NPC1L1 knockout mice. These results unequivocally establish NPC1L1 as the direct target of ezetimibe and should facilitate efforts to identify the molecular mechanism of cholesterol transport.

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  • Ezetimibe blocks the intestinal cholesterol transporter NPC1L1 that mediates cholesterol absorption.

    “Ezetimibe blocks the intestinal cholesterol transporter Niemann Pick C1-Like 1 (NPC1L1) that mediates cholesterol absorption6”

    From Pathways and Molecular Mechanisms Governing LDL Receptor Regulation (2025) · cites this paper as [6]

    The Results and Discussion establish NPC1L1 as ezetimibe’s direct target and say that ezetimibe binding blocks intestinal cholesterol absorption. But the same section says it remains unresolved whether NPC1L1 is the cholesterol transporter itself or a regulatory component that indirectly affects transport. Calling it the transporter overstates the paper’s finding. (LLM, conf=0.90)

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  • NPC1L1 is a target of the drug ezetimibe.

    “NPC1L1 is a target of the drug ezetimibe (EZ) (8–10).”

    From Aster-dependent nonvesicular transport facilitates dietary cholesterol uptake (2023) · cites this paper as [8]

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Research works printed but not linked: 31

  1. 10.1146/annurev.nu.03.070183.000443 · DOI
  2. 10.1021/jm030283g · DOI · Paper page
  3. 10.1074/jbc.M405817200 · DOI · Paper page
  4. 10.1016/S0149-2918(01)80102-8 · DOI
  5. 10.1016/S0002-9149(02)02798-4 · DOI
  6. 10.1016/S0195-668X(02)00807-2 · DOI
  7. 10.1016/S0002-9149(02)02774-1 · DOI
  8. 10.1016/S0002-9149(02)03236-8 · DOI
  9. Melani, L., Mills, R., Hassman, D., Lipetz, R., Lipka, L., LeBeaut, A., Suresh, R., Mukhopadhyay, P. & Veltri, E. (2003) Eur. Heart J. 24, 717-728.12713766
  10. 10.1016/S0735-1097(02)02610-4 · DOI
  11. 10.1161/01.CIR.0000068312.21969.C8 · DOI
  12. 10.1126/science.1095519 · DOI
  13. 10.1126/science.290.5497.1771 · DOI
  14. 10.1126/science.289.5484.1524 · DOI
  15. 10.1016/S0960-894X(01)00752-1 · DOI
  16. 10.1016/S1388-1981(01)00190-1 · DOI
  17. 10.1038/35089558 · DOI
  18. 10.1006/geno.2000.6151 · DOI
  19. 10.1126/science.1093131 · DOI
  20. 10.1016/0005-2736(80)90335-1 · DOI
  21. 10.1016/S0021-9258(17)46808-6 · DOI
  22. 10.1021/bi00126a011 · DOI
  23. Weiland, G. A. & Molinoff, P. B. (1981) Life Sci. 27, 29313-29330.
  24. Van Heek, M., France, C. F., Compton, D. S., McLeod, R. L., Yumibe, N. P., Alton, K. B., Sybertz, E. J. & Davis, H. R., Jr., (1997) J. Pharmacol. Exp. Ther. 283, 157-163.9336320
  25. 10.1161/hq1201.100260 · DOI · Paper page
  26. 10.2174/0929867043364865 · DOI
  27. 10.1016/S0149-2918(03)80281-3 · DOI
  28. 10.1073/pnas.0400441101 · DOI
  29. 10.1074/jbc.M406309200 · DOI
  30. 10.1073/pnas.96.20.11041 · DOI · Paper page
  31. 10.1016/j.molcel.2004.06.019 · DOI · Paper page

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Metadata

Authors
Garcia-Calvo, M., Lisnock, J., Bull, H. G., Hawes, B. E., Burnett, D. A., Braun, M. P., Crona, J. H., Davis, H. R., Dean, D. C., Detmers, P. A., Graziano, M. P., Hughes, M., MacIntyre, D. E., Ogawa, A., O'Neill, K. A., Iyer, S. P. N., Shevell, D. E., Smith, M. M., Tang, Y. S., Makarewicz, A. M., Ujjainwalla, F., Altmann, S. W., Chapman, K. T., & Thornberry, N. A.
Affiliations
Departments of Metabolic Disorders, Drug Metabolism Labeled Compound Synthesis, Immunology, Pharmacology, Medicinal Chemistry, and Target Validation, Merck Research Laboratories, Rahway, NJ 07065; and Departments of Cardiovascular/Metabolic Diseases, Chemistry, and Discovery Technologies, Schering-Plough Research Institute, Kenilworth, NJ 07033
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2005-05-31
Volume
102
Issue
23
Pages
8132-8137
ISSN
  • 0027-8424
  • 1091-6490
DOI
10.1073/pnas.0500269102
Cited by
670
References
1
Language
en

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