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Lipid metabolism, remodelling and intercellular transfer in the CNS

Nature Reviews Neuroscience volume 26, pages 214–231 (2025)Cite this article

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Abstract

Lipid metabolism encompasses the catabolism and anabolism of lipids, and is fundamental for the maintenance of cellular homeostasis, particularly within the lipid-rich CNS. Increasing evidence further underscores the importance of lipid remodelling and transfer within and between glial cells and neurons as key orchestrators of CNS lipid homeostasis. In this Review, we summarize and discuss the complex landscape of processes involved in lipid metabolism, remodelling and intercellular transfer in the CNS. Highlighted are key pathways, including those mediating lipid (and lipid droplet) biogenesis and breakdown, lipid oxidation and phospholipid metabolism, as well as cell–cell lipid transfer mediated via lipoproteins, extracellular vesicles and tunnelling nanotubes. We further explore how the dysregulation of these pathways contributes to the onset and progression of neurodegenerative diseases, and examine the homeostatic and pathogenic impacts of environment, diet and lifestyle on CNS lipid metabolism.

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Fig. 1: Lipid metabolism and remodelling in the CNS.
Fig. 2: Intercellular lipid transfer in the CNS.

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Acknowledgements

The authors thank all members of the Bogie, Hendriks and Miron laboratories for the discussions. The research of S.V. is funded by the FWO Vlaanderen (1246724N) and Charcot Research Foundation (CHARCO24VS). V.E.M is funded by the John David Eaton Chair in Multiple Sclerosis Research (Barlo MS Centre, St. Michael’s Hospital Foundation), the Sloan-Hall MS Basic Research Fund, MS Canada and a Senior Non-Clinical Research Fellowship from the Medical Research Council. J.J.A.H is funded by the Research Foundation of Flanders (FWO Vlaanderen; G0A7922, G0A7922, S01623N) and the Charcot Research Foundation (CHARCO23HJ, CHARCO24HJ). J.F.J.B is funded by the Research Foundation of Flanders (FWO Vlaanderen; G075823, G0A3B24), Charcot Research Foundation (CHARCO23BJ, CHARCO24BJ), Geneeskundige Stichting Koningin Elisabeth (G.S.K.E; GSKE-BOGJ), MS Liga Vlaanderen (MSLIGABOGJ) and the special research fund Hasselt University (22DOC38BOF, 23INC06BOF).

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Authors and Affiliations

  1. Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Hasselt, Belgium

    Sam Vanherle, Melanie Loix, Jerome J. A. Hendriks & Jeroen F. J. Bogie

  2. University MS Centre, Hasselt University, Hasselt, Belgium

    Sam Vanherle, Melanie Loix, Jerome J. A. Hendriks & Jeroen F. J. Bogie

  3. Keenan Research Centre for Biomedical Science and Barlo Multiple Sclerosis Centre, St Michael’s Hospital, Toronto, Ontario, Canada

    Veronique E. Miron

  4. Department of Immunology, The University of Toronto, Toronto, Ontario, Canada

    Veronique E. Miron

  5. UK Dementia Research Institute at The University of Edinburgh, Edinburgh, UK

    Veronique E. Miron

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  1. Sam Vanherle
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  3. Veronique E. Miron
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J.F.J.B. and S.V. contributed substantially to discussion of the content. All authors wrote the article and reviewed and/or edited the manuscript before submission.

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Glossary

β-Oxidation

The metabolic pathway that breaks down fatty acids (FAs) into acetyl-CoA units in the mitochondria for energy production.

Autophagy

A cellular process in which damaged or unnecessary components of the cell are degraded and recycled within the cell through lysosomal activity.

Cholesterol

A lipid molecule synthesized in all cell types, essential for cell membrane structure, hormone synthesis and bile acid formation.

Extracellular vesicles

(EVs). Nanosized lipid bilayer particles secreted by cells that carry lipids, proteins and RNA to distant and nearby cells, playing a key role in intercellular communication.

Fatty acid

(FA). A carboxylic acid consisting of a hydrocarbon chain and a terminal carboxyl group, essential for energy storage and membrane structure.

Lipid droplets

Intracellular storage organelles primarily composed of neutral lipids such as triglycerides, serving as energy reserves.

Lipidome

The complete set of lipids in a biological system, encompassing various lipid classes.

Lipoproteins

Complexes of lipids and proteins with a hydrophobic core that transport lipids, such as cholesterol and triglycerides, through the bloodstream.

Monounsaturated fatty acids

(MUFAs). Fatty acids (FAs) with one unsaturated carbon bond in their hydrocarbon chain, commonly found in olive oil and avocados.

Phospholipids

Lipids containing a phosphate group, forming the structural components of cell membranes.

Polyunsaturated fatty acids

(PUFAs). Fatty acids (FAs) with two or more double bonds in their hydrocarbon chain, important for membrane fluidity and signalling.

Saturated fatty acids

(SFAs). Fatty acids (FAs) with no double bonds in their hydrocarbon chain, typically solid at room temperature and found in animal fats.

Tracer lipidomics

A method for studying lipid metabolism by tracking the incorporation of labelled lipid precursors into biological systems.

Western diet

A dietary pattern high in processed foods, fats (such as saturated fats and cholesterol) and sugars, and low in fibre, commonly associated with various chronic diseases.

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Vanherle, S., Loix, M., Miron, V.E. et al. Lipid metabolism, remodelling and intercellular transfer in the CNS. Nat. Rev. Neurosci. 26, 214–231 (2025). https://doi.org/10.1038/s41583-025-00908-3

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