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Flotillins play an essential role in Niemann-Pick C1-like 1-mediated cholesterol uptake
Open accessAbstract
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.
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Cited by
Mechanisms and regulation of cholesterol homeostasis
Luo, J., Yang, H., & Song, B.-L. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0190-7 · Cited by 1,980
Self-citationRegulation of intestinal lipid metabolism: current concepts and relevance to disease
Ko, C.-W., Qu, J., Black, D. D., & Tso, P. (2020) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-019-0250-7 · Cited by 510
Role of the Gut in Lipid Homeostasis
Abumrad, N. A., & Davidson, N. O. (2012) · Physiological Reviews · doi:10.1152/physrev.00019.2011 · Cited by 355
Structural insights into the mechanism of human NPC1L1-mediated cholesterol uptake
Hu, M., Yang, F., Huang, Y., You, X., Liu, D., Sun, S., & Sui, S.-F. (2021) · Science Advances · doi:10.1126/sciadv.abg3188 · Cited by 72
Ezetimibe blocks the internalization of NPC1L1 and cholesterol in mouse small intestine
Xie 谢畅, C., Zhou 周章森, Z.-S., Li 李钠, N., Bian 卞艳, Y., Wang 王永建, Y.-J., Wang 王丽娟, L.-J., Li 李伯良, B.-L., & Song 宋保亮, B.-L. (2012) · Journal of Lipid Research · doi:10.1194/jlr.m027359 · Cited by 64
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Metadata
- Authors
- Ge, L., Qi, W., Wang, L.-J., Miao, H.-H., Qu, Y.-X., Li, B.-L., & Song, B.-L.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2010-12-27
- Volume
- 108
- Issue
- 2
- Pages
- 551-556
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2105641097
- Cited by
- 162
- References
- 0
- FWCI
- 10.56
- Type
- journal article
- Language
- en
- Open access
- green
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- Ge, L., Qi, W., Wang, L.-J., Miao, H.-H., Qu, Y.-X., Li, B.-L., & Song, B.-L. (2011). Flotillins play an essential role in Niemann-Pick C1-like 1-mediated cholesterol uptake. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.1014434108
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