Blood-Brain Barrier Permeability Is Regulated by Lipid Transport-Dependent Suppression of Caveolae-Mediated Transcytosis
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The blood-brain barrier (BBB) provides a constant homeostatic brain environment that is essential for proper neural function. An unusually low rate of vesicular transport (transcytosis) has been identified as one of the two unique properties of CNS endothelial cells, relative to peripheral endothelial cells, that maintain the restrictive quality of the BBB. However, it is not known how this low rate of transcytosis is achieved. Here we provide a mechanism whereby the regulation of CNS endothelial cell lipid composition specifically inhibits the caveolae-mediated transcytotic route readily used in the periphery. An unbiased lipidomic analysis reveals significant differences in endothelial cell lipid signatures from the CNS and periphery, which underlie a suppression of caveolae vesicle formation and trafficking in brain endothelial cells. Furthermore, lipids transported by Mfsd2a establish a unique lipid environment that inhibits caveolae vesicle formation in CNS endothelial cells to suppress transcytosis and ensure BBB integrity.
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Knockout of murine Mfsd2a gene results in diminished brain uptake of docosahexaenoic acid (DHA) in the form of lysophosphatidylcholine and leads to dysregulated caveolae-mediated transcellular trafficking across the BBB causing BBB breakdown.
“whereas knockout of murine Mfsd2a gene results in not only diminished brain uptake of docosahexaenoic acid (DHA) in the form of lysophosphatidylcholine, but also leads to dysregulated caveolae-mediated transcellular trafficking across the BBB causing BBB breakdown (21, 62, 684).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [21]
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- Authors
- Andreone, B. J., Chow, B. W., Tata, A., Lacoste, B., Ben-Zvi, A., Bullock, K., Deik, A. A., Ginty, D. D., Clish, C. B., & Gu, C.
- Affiliations
- Harvard University (US)
- Broad Institute (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Gu, Chenghua
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2017-05
- Volume
- 94
- Issue
- 3
- Pages
- 581-594.e5
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC5474951
- OpenAlex
- W2606840533
- Cited by
- 636
- References
- 4
- Citations by year
- 2026: 80 · 2025: 70 · 2024: 87 · 2023: 70 · 2022: 79 · 2021: 72 · 2020: 77 · 2019: 39 · 2018: 39 · 2017: 20 · 2015: 1 · 2012: 1
- FWCI
- 23.84
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 367 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (F31NS090669, DP1 NS092473)
- Mahoney postdoctoral fellowship
- Howard Hughes Medical Institute
- Kaneb Fellowship
- Fidelity Biosciences Research Initiative
- Harvard Blavatnik Biomedical Accelerator
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Caveolin-1 and cellular processes
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- blood-brain barrier, transcytosis, caveolae, lipid transport, MFSD2A, vesicle trafficking, lipidomics, blood-brain barrier permeability
- MeSH terms
- Animals, Blood-Brain Barrier, Humans, Immunohistochemistry, Permeability, Blotting, Western, Mice, Knockout, Microscopy, Confocal, Caveolae, Membrane Transport Proteins, Symporters, Endothelial Cells, Microscopy, Electron, Transmission, Lipid Metabolism, Mice, HEK293 Cells, Transcytosis
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