The cholesterol absorption inhibitor ezetimibe acts by blocking the sterol-induced internalization of NPC1L1.
Niemann-Pick C1-like 1 (NPC1L1) is a polytopic transmembrane protein that plays a critical role in cholesterol absorption. Ezetimibe, a hypocholesterolemic drug, has been reported to bind NPC1L1 and block cholesterol absorption. However, the molecular mechanism of NPC1L1-mediated cholesterol uptake and how ezetimibe inhibits this process are poorly defined. Here we find that cholesterol specifically promotes the internalization of NPC1L1 and that this process requires microfilaments and the clathrin/AP2 complex. Blocking NPC1L1 endocytosis dramatically decreases cholesterol internalization, indicating that NPC1L1 mediates cholesterol uptake via its vesicular endocytosis. Ezetimibe prevents NPC1L1 from incorporating into clathrin-coated vesicles and thus inhibits cholesterol uptake. Together, our data suggest a model wherein cholesterol is internalized into cells with NPC1L1 through clathrin/AP2-mediated endocytosis and ezetimibe inhibits cholesterol absorption by blocking the internalization of NPC1L1.
State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Liang
L
Ge
Jing
J
Wang
Wei
W
Qi
Hong-Hua
HH
Miao
Jian
J
Cao
Yu-Xiu
YX
Qu
Bo-Liang
BL
Li
Bao-Liang
BL
Song
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D001384:Azetidines / Q000494:pharmacology*; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism* / Q000502:physiology; D022163:Clathrin-Coated Vesicles / Q000378:metabolism; D003001:Cloning, Molecular; D004705:Endocytosis / Q000187:drug effects*; D000069438:Ezetimibe; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects*; D008099:Liver / Q000166:cytology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins; D051381:Rats
D000924:Anticholesteremic Agents; D001384:Azetidines; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C410800:NPC1L1 protein, human; D002784:Cholesterol; D000069438:Ezetimibe