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Endothelial gateways for brain lipid uptake and metabolism
A. Dushani Ranasinghe, Timothy Hla
A. Dushani Ranasinghe, Timothy Hla
Published October 1, 2025
Citation Information: J Clin Invest. 2025;135(19):e198352. https://doi.org/10.1172/JCI198352.
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Commentary

Endothelial gateways for brain lipid uptake and metabolism

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Abstract

Lipids, which constitute half of the brain’s solid matter, are essential for forming specialized membranes of neural cells, providing energy sources, and facilitating cell-to-cell communication. Although the blood-brain barrier restricts lipid movement between peripheral circulation and the brain, multiple mechanisms supply the building blocks necessary to synthesize the diverse lipid species present in the central nervous system (CNS). In this issue of the JCI, Song et al. characterize specialized microvascular niches that metabolize circulating triglyceride-rich lipoproteins (TRLs) to deliver fatty acids into the brain. They located GPIHBP1, an essential chaperone for lipoprotein lipase (LPL) in the fenestrated endothelial cells of the choroid plexus (ChP) and circumventricular organs (CVOs), demonstrating lipolytic processing of peripheral TRLs and brain uptake of fatty acids. This advance implicates the GPIHBP1/LPL lipid metabolic hub in supporting the roles of the ChP and CVO in cerebrospinal fluid composition, immunity, satiety, thirst, and metabolic homeostasis.

Authors

A. Dushani Ranasinghe, Timothy Hla

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Figure 1

Schematic illustration of fatty acid uptake at the choroid plexus blood-brain barrier.

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Schematic illustration of fatty acid uptake at the choroid plexus blood-...
The choroid plexus (ChP) forms a network lining capillaries within the brain’s ventricles. The endothelium of the ChP is characterized by specialized pores called fenestrae that selectively exchange substances between the blood and tissue. Work by Song et al. revealed that circulating triglyceride-rich lipoproteins (TRLs) in the blood interact with endothelial lipoprotein lipase (LPL) on the luminal surface glycocalyx, a process that requires the chaperone GPIHBP1. LPL hydrolyzes TRLs, releasing fatty acids (FAs) that cross the fenestrated ChP endothelium into the tissue. This process highlights a specialized CNS vascular mechanism for lipid uptake and signaling at the ChP. The fate of released FAs, their role in disease (such as Alzheimer’s disease), and mechanisms underlying TRL clearance are valid and important questions to be answered in the future.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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