Molecular Characterization of the NPC1L1 Variants Identified from Cholesterol Low Absorbers

	Molecular Characterization of the NPC1L1 Variants Identified from Cholesterol Low Absorbers
	Wang, LJ; Wang, J; Li, N; Ge, LA; Li, BL; Song, BL
刊名	JOURNAL OF BIOLOGICAL CHEMISTRY
	2011
卷号	286 期号:9 页码:7397-7408
通讯作者	Song, BL (reprint author), Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, State Key Lab Mol Biol, 320 Yue Yang Rd, Shanghai 200031, Peoples R China.,blsong@sibs.ac.cn
英文摘要	Niemann-Pick C1-like 1 (NPC1L1) is an essential protein for dietary cholesterol absorption. Nonsynonymous (NS) variants of NPC1L1 in humans have been suggested to associate with cholesterol absorption variations. However, information concerning the characteristics and mechanism of these variants in cholesterol uptake is limited. In this study, we analyzed the cholesterol uptake ability of the 19 reported NS variants of NPC1L1 identified from cholesterol low absorbers. Among these variants, L110F, R306C, A395V, G402S, T413M, R693C, R1214H, and R1268H could partially mediate cellular cholesterol uptake and were categorized as partially dysfunctional variants. The other 11 variants including T61M, N132S, D398G, R417W, G434R, T499M, S620C, I647N, G672R, S881L, and R1108W could barely facilitate cholesterol uptake, and were classified into the severely dysfunctional group. The partially dysfunctional variants showed mild defects in one or multiple aspects of cholesterol-regulated recycling, subcellular localization, glycosylation, and protein stability. The severely dysfunctional ones displayed remarkable defects in all these aspects and were rapidly degraded through the ER-associated degradation (ERAD) pathway. In vivo analyses using adenovirus-mediated expression in mouse liver confirmed that the S881L variant failed to localize to liver canalicular membrane, and the mice showed defects in biliary cholesterol re-absorption, while the G402S variant appeared to be similar to wildtype NPC1L1 in mouse liver. This study suggests that the dysfunction of the 19 variants on cholesterol absorption is due to the impairment of recycling, subcellular localization, glycosylation, or stability of NPC1L1.
学科主题	Biochemistry & Molecular Biology
类目[WOS]	Biochemistry & Molecular Biology
关键词[WOS]	LOW-DENSITY-LIPOPROTEIN ; RECOMBINANT ADENOVIRUSES ; GENETIC-VARIATION ; ABSORPTION ; EZETIMIBE ; PROTEIN ; METABOLISM ; TRANSPORT ; MEMBRANE ; COMPLEX
收录类别	SCI
语种	英语
WOS记录号	WOS:000287737300055
内容类型	期刊论文
版本	出版稿
源URL	[http://202.127.25.143/handle/331003/852]
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, LJ,Wang, J,Li, N,et al. Molecular Characterization of the NPC1L1 Variants Identified from Cholesterol Low Absorbers[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2011,286(9):7397-7408.
APA	Wang, LJ,Wang, J,Li, N,Ge, LA,Li, BL,&Song, BL.(2011).Molecular Characterization of the NPC1L1 Variants Identified from Cholesterol Low Absorbers.JOURNAL OF BIOLOGICAL CHEMISTRY,286(9),7397-7408.
MLA	Wang, LJ,et al."Molecular Characterization of the NPC1L1 Variants Identified from Cholesterol Low Absorbers".JOURNAL OF BIOLOGICAL CHEMISTRY 286.9(2011):7397-7408.