title: Flotillins play an essential role in Niemann-Pick C1-like 1-mediated cholesterol uptake.
abstract: Dietary absorption is a major way for mammals to obtain cholesterol, which is mediated by Niemann-Pick C1-like 1 (NPC1L1) via vesicular endocytosis. One fundamental question in this process is how free cholesterol is efficiently taken up through the internalization of NPC1L1. Using exogenously expressed NPC1L1-EGFP, we show that the lipid raft proteins flotillins associate with NPC1L1 and their localization is regulated by NPC1L1 during intracellular trafficking. Furthermore, flotillins are essential for NPC1L1-mediated cellular cholesterol uptake, biliary cholesterol reabsorption, and the regulation of lipid levels in mice. Together with NPC1L1, they form cholesterol-enriched membrane microdomains, which function as carriers for bulk of cholesterol. The hypocholesterolemic drug ezetimibe disrupts the association between NPC1L1 and flotillins, which blocks the formation of the cholesterol-enriched microdomains. Our findings reveal a functional role of flotillins in NPC1L1-mediated cholesterol uptake and elucidate the formation of NPC1L1-flotillins-postive cholesterol-enriched membrane microdomains as a mechanism for efficient cholesterol absorption.
authors.affiliation: State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Ge
authors.forename: Wei
authors.initials: W
authors.lastname: Qi
authors.forename: Li-Juan
authors.initials: LJ
authors.lastname: Wang
authors.forename: Hong-Hua
authors.initials: HH
authors.lastname: Miao
authors.forename: Yu-Xiu
authors.initials: YX
authors.lastname: Qu
authors.forename: Bo-Liang
authors.initials: BL
authors.lastname: Li
authors.forename: Bao-Liang
authors.initials: BL
authors.lastname: Song
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D001384:Azetidines / Q000494:pharmacology; D002784:Cholesterol / Q000737:chemistry / Q000378:metabolism*; D000069438:Ezetimibe; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal / Q000379:methods; D008856:Microscopy, Fluorescence / Q000379:methods; D009542:Niemann-Pick Diseases / Q000378:metabolism*; D051381:Rats
chemical_list: D000924:Anticholesteremic Agents; D001384:Azetidines; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C410800:NPC1L1 protein, human; C482444:NPC1L1 protein, rat; C482445:Npc1l1 protein, mouse; C106354:flotillins; D049452:Green Fluorescent Proteins; D002784:Cholesterol; D000069438:Ezetimibe