The cholesterol absorption inhibitor ezetimibe acts by blocking the sterol-induced internalization of NPC1L1

被引：315

作者：

Ge, Liang ^{[1
]}

Wang, Jing ^{[1
]}

Qi, Wei ^{[2
]}

Miao, Hong-Hua ^{[1
]}

Cao, Jian ^{[1
]}

Qu, Yu-Xiu ^{[1
]}

Li, Bo-Liang ^{[1
]}

Song, Bao-Liang ^{[1
]}

机构：

[1] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, State Key Lab Mol Biol, Shanghai 200031, Peoples R China

[2] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Nutr Sci, Key Lab Nutr & Metab, Shanghai 200031, Peoples R China

来源：

CELL METABOLISM | 2008年 / 7卷 / 06期

基金：

中国国家自然科学基金;

关键词：

D O I：

10.1016/j.cmet.2008.04.001

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：508 / 519

页数：12

共 47 条

[1] Niemann-Pick C1 like 1 protein is critical for intestinal cholesterol absorption [J].