Flotillins play an essential role in Niemann-Pick C1-like 1-mediated cholesterol uptake
- 27 December 2010
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 108 (2), 551-556
- https://doi.org/10.1073/pnas.1014434108
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.Keywords
This publication has 28 references indexed in Scilit:
- Hetero-oligomerization of reggie-1/flotillin-2 and reggie-2/flotillin-1 is required for their endocytosisCellular Signalling, 2009
- Extracellular loop C of NPC1L1 is important for binding to ezetimibeProceedings of the National Academy of Sciences of the United States of America, 2008
- The Cholesterol Absorption Inhibitor Ezetimibe Acts by Blocking the Sterol-Induced Internalization of NPC1L1Cell Metabolism, 2008
- Dissecting the molecular function of reggie/flotillin proteinsEuropean Journal of Cell Biology, 2007
- Glut-4 is translocated to both caveolae and non-caveolar lipid rafts, but is partially internalized through caveolae in insulin-stimulated adipocytesCell Research, 2007
- The SPFH domain-containing proteins: more than lipid raft markersTrends in Cell Biology, 2007
- Detergent resistance as a tool in membrane researchNature Protocols, 2007
- Hepatic Niemann-Pick C1–like 1 regulates biliary cholesterol concentration and is a target of ezetimibeJCI Insight, 2007
- Cholesterol Sensing, Trafficking, and EsterificationAnnual Review of Cell and Developmental Biology, 2006
- Cholesterol-regulated Translocation of NPC1L1 to the Cell Surface Facilitates Free Cholesterol UptakeOnline Journal of Public Health Informatics, 2006