| Autor: |
Garcia-Calvo, Margarita, Lisnock, JeanMarie, Bull, Herbert G., Hawes, Brian E., Burnett, Duane A., Braun, Matthew P., Crona, James H., Davis, Jr, Harry R., Dean, Dennis C., Detmers, Patricia A., Graziano, Michael P., Hughes, Meredith, Euan Madntyre, D., Ogawa, Anthony, O'Neill, Kim A., Lyer, Sai Prasad N., Shevell, Diane E., Smith, Marsha M., Tang, Yui S., Makarewicz, Amanda M. |
| Předmět: |
|
| Zdroj: |
Proceedings of the National Academy of Sciences of the United States of America; 6/7/2005, Vol. 102 Issue 23, p8132-8137, 6p |
| Abstrakt: |
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 Cl-Like I (NPCILI) 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 NPC1LI. Moreover, the binding affinities of ezetimibe and several key analogs to recombinant NPCILI are virtually identical to those observed for native enterocyte membranes. KD values of ezetimibe glucuronide for mouse, rat rhesus monkey, and human NPCILI are 12,000,540, 40, and 220 nM, respectively. Last, ezetimibe no longer binds to membranes from NPC1L1 knockout mice. These results unequivocally establish NPCILI as the direct target of ezetimibe and should facilitate efforts to identify the molecular mechanism of cholesterol transport. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
|
