Membrane topology of human NPC1L1, a key protein in enterohepatic cholesterol absorption

	Membrane topology of human NPC1L1, a key protein in enterohepatic cholesterol absorption
	Wang, J; Chu, BB; Ge, L; Li, BL; Yan, Y; Song, BL
刊名	JOURNAL OF LIPID RESEARCH
	2009
卷号	50 期号:8 页码:1653-1662
关键词	ezetimibe NPC1 Niemann-Pick C1 Like 1 SSD
通讯作者	Yan, Y (reprint author), Fudan Univ, Zhongshan Hosp, Shanghai Inst Cardiovasc Dis, Shanghai 200433, Peoples R China.,jackyan000@hotmail.com ; blsong@sibs.ac.cn
英文摘要	The Niemann-Pick C1 Like 1 (NPC1L1) is a predicted polytopic membrane protein that is critical for cholesterol absorption. NPC1L1 takes up free cholesterol into cells through vesicular endocytosis. Ezetimibe, a clinically used cholesterol absorption inhibitor, blocks the endocytosis of NPC1L1 thereby inhibiting cholesterol uptake. Human NPC1L1 is a 1,332-amino acid protein with a putative sterol-sensing domain (SSD) that shows sequence homology to HMG-CoA reductase (HMGCR), Niemann-Pick C1 (NPC1), and SREBP cleavage-activating protein (SCAP). Here, we use protease protection and immunofluorescence in selectively permeabilized cells to study the topology of human NPC1L1. Our data indicate that NPC1L1 contains 13 transmembrane helices. The NH(2)-terminus of NPC1L1 is in the lumen while the COOH-terminus projects to the cytosol. human NPC1L1 contains seven small cytoplasmic loops-four small and three large luminal loops-one of which has been reported to bind ezetimibe. Ezetimibe-glucuronide, the major metabolite of ezetimibe in vivo, can block the internalization of NPC1L1 and cholesterol. The membrane topology of NPC1L1 is similar to that of NPC1, and the putative SSD of NPC1L1 is oriented in the same manner as those of HMGCR, NPC1, and SCAP. The defined topology of NPC1L1 provides necessary information for further dissecting the functions of the different domains of NPC1L1-Wang, J., B-B. Chu, L. Ge, B-L. Li, Y. Yan, and B-L. Song. Membrane topology of human NPC1L1, a key protein in enterohepatic cholesterol absorption. J. Lipid Res. 2009. 50: 1653-1662.
学科主题	Biochemistry & Molecular Biology
类目[WOS]	Biochemistry & Molecular Biology
关键词[WOS]	STEROL-SENSING DOMAIN ; HMG-COA REDUCTASE ; CLEAVAGE-ACTIVATING PROTEIN ; PICK C1 PROTEIN ; 3-HYDROXY-3-METHYLGLUTARYL-COA REDUCTASE ; BINDING ; EZETIMIBE ; HOMEOSTASIS ; INSIG-1 ; DISEASE
收录类别	SCI
语种	英语
WOS记录号	WOS:000267949900016
内容类型	期刊论文
版本	出版稿
源URL	[http://202.127.25.143/handle/331003/1228]
专题	上海生化细胞研究所_上海生科院生化细胞研究所
推荐引用方式 GB/T 7714	Wang, J,Chu, BB,Ge, L,et al. Membrane topology of human NPC1L1, a key protein in enterohepatic cholesterol absorption[J]. JOURNAL OF LIPID RESEARCH,2009,50(8):1653-1662.
APA	Wang, J,Chu, BB,Ge, L,Li, BL,Yan, Y,&Song, BL.(2009).Membrane topology of human NPC1L1, a key protein in enterohepatic cholesterol absorption.JOURNAL OF LIPID RESEARCH,50(8),1653-1662.
MLA	Wang, J,et al."Membrane topology of human NPC1L1, a key protein in enterohepatic cholesterol absorption".JOURNAL OF LIPID RESEARCH 50.8(2009):1653-1662.