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Cited by 239Lipid Membrane Structure and BehaviorCholesterol and Lipid MetabolismCancer, Lipids, and Metabolism

Orthogonal lipid sensors identify transbilayer asymmetry of plasma membrane cholesterol

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Liu, Shu-Lin, Sheng, Ren, Jung, Jae Hun, Wang, Li, Stec, Ewa, O'Connor, Matthew J, Song, Seohyoen, Bikkavilli, Rama Kamesh +7 more·2017·Nature Chemical Biology
DOI 10.1038/nchembio.2268PMC PMC5912897
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Abstract

Controlled distribution of lipids across various cell membranes is crucial for cell homeostasis and regulation. We developed an imaging method that allows simultaneous in situ quantification of cholesterol in two leaflets of the plasma membrane (PM) using tunable orthogonal cholesterol sensors. Our imaging revealed marked transbilayer asymmetry of PM cholesterol (TAPMC) in various mammalian cells, with the concentration in the inner leaflet (IPM) being ∼12-fold lower than that in the outer leaflet (OPM). The asymmetry was maintained by active transport of cholesterol from IPM to OPM and its chemical retention at OPM. Furthermore, the increase in the IPM cholesterol level was triggered in a stimulus-specific manner, allowing cholesterol to serve as a signaling lipid. We found excellent correlation between the IPM cholesterol level and cellular Wnt signaling activity, suggesting that TAPMC and stimulus-induced PM cholesterol redistribution are crucial for tight regulation of cellular processes under physiological conditions.

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  • Certain PZD-domain containing proteins such as Dvl2 can be directly activated by cholesterol within the inner leaflet of the plasma membrane.

    “Recent reports suggest that certain PZD-domain containing proteins such as Dvl2 can be directly activated by cholesterol within the inner leaflet of the plasma membrane (43, 44, 82–84).”

    From Cholesterol efflux protein, ABCA1, supports anticancer functions of myeloid immune cells (2026) · cites this paper as [83]

    The Results section ('Stimulus-dependent redistribution of PM cholesterol'; page unavailable) reports that an increase in inner-leaflet cholesterol correlates with Dvl2 recruitment to the plasma membrane, and cites an earlier report of cholesterol-dependent Dvl activation. It does not show that inner-leaflet cholesterol directly activates Dvl2 or establish the proposed PDZ-domain mechanism. (LLM, conf=0.83)

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Cited by

Sorted by citations

Authors
Liu, S.-L., Sheng, R., Jung, J. H., Wang, L., Stec, E., O'Connor, M. J., Song, S., Bikkavilli, R. K., Winn, R. A., Lee, D., Baek, K., Ueda, K., Levitan, I., Kim, K.-P., & Cho, W.
Affiliations
  • University of Illinois Chicago (US)
  • Kyung Hee University (KR)
  • Kyoto University (JP)
Corresponding author
Cho, Wonhwa
ORCID
Venue
Nature Chemical Biology
Publisher
Springer Science and Business Media LLC
Published
2016-12-26
Volume
13
Issue
3
Pages
268-274
ISSN
  • 1552-4450 (ISSN-L)
  • 1552-4469
DOI
10.1038/nchembio.2268
PMC
PMC5912897
OpenAlex
W2564133151
Cited by
239
References
3
Citations by year
2026: 13 · 2025: 27 · 2024: 18 · 2023: 35 · 2022: 26 · 2021: 27 · 2020: 32 · 2019: 22 · 2018: 28 · 2017: 11
FWCI
10.57
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Chemical Biology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Japan Society for the Promotion of Science (25221203)
  • National Heart, Lung, and Blood Institute (R01HL073965, R01HL083298)
  • National Cancer Institute (U54CA202995, U54CA203000, U54CA202997)
  • National Institute of General Medical Sciences (R01GM068849, R01GM110128, R35GM122530)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Keywords
plasma membrane cholesterol, cholesterol transport, Wnt signaling, signaling lipids, membrane lipid distribution
MeSH terms
Cell Line, Cell Membrane, Cholesterol, Humans, Lipids, HEK293 Cells

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