Interaction of sortilin with apolipoprotein E3 enables neurons to use long-chain fatty acids as alternative metabolic fuel
A. Gręda, Jemila P. Gomes, Vanessa Schmidt, Ewa Żurawska-Płaksej, Raphaela Fritsche‐Guenther, Ina‐Maria Rudolph, Narasimha Swamy Telugu, Cagla Cömert et al.. Nature Metabolism, 2025-10-16
Topic: Brain proteins, microglia and lab models
Sortilin (SORT1) is a lipoprotein receptor that shows genome-wide association with hypercholesterolaemia, explained by its ability to control hepatic output of lipoproteins. Although SORT1 also shows genome-wide association with Alzheimer disease and frontotemporal lobe dementia, the most prevalent forms of age-related dementias, sortilin's contribution to human brain lipid metabolism and health remains unclear. Here we show that sortilin mediates neuronal uptake of polyunsaturated fatty acids carried by apolipoprotein E (apoE). Using humanized mouse strains and induced pluripotent stem cell-based cell models of brain lipid homeostasis, we demonstrate that internalized lipids are converted into ligands for peroxisome proliferator-activated receptor alpha inducing transcription profiles that enable neurons to use long-chain fatty acids as metabolic fuel when glucose is limited. This pathway works with apoE3 but cannot operate with the Alzheimer disease risk factor apoE4, which disrupts sortilin's endocytic activity. Our data indicate a role for the lipoprotein receptor sortilin in metabolic fuel choice in neurons, which may be crucial when glucose supply is limited, such as in the ageing brain.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Gręda, A., Gomes, J. P., Schmidt, V., Żurawska-Płaksej, E., Fritsche‐Guenther, R., Rudolph, I., et al. (2025). Interaction of sortilin with apolipoprotein E3 enables neurons to use long-chain fatty acids as alternative metabolic fuel. Nature Metabolism. https://doi.org/10.1038/s42255-025-01389-5
Vancouver
Gręda A, Gomes JP, Schmidt V, Żurawska-Płaksej E, Fritsche‐Guenther R, Rudolph I, et al. Interaction of sortilin with apolipoprotein E3 enables neurons to use long-chain fatty acids as alternative metabolic fuel. Nature Metabolism. 2025. doi:10.1038/s42255-025-01389-5. PMID: 41102453.
BibTeX
@article{greda2025-41102453,
author = {Gręda, A. and Gomes, Jemila P. and Schmidt, Vanessa and Żurawska-Płaksej, Ewa and Fritsche‐Guenther, Raphaela and Rudolph, Ina‐Maria and Telugu, Narasimha Swamy and Cömert, Cagla and others},
title = {{Interaction of sortilin with apolipoprotein E3 enables neurons to use long-chain fatty acids as alternative metabolic fuel}},
journal = {Nature Metabolism},
year = {2025},
doi = {10.1038/s42255-025-01389-5},
pmid = {41102453},
url = {https://doi.org/10.1038/s42255-025-01389-5}
}
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
Key findings
- Although SORT1 also shows genome-wide association with Alzheimer disease and frontotemporal lobe dementia, the most prevalent forms of age-related dementias, sortilin's contribution to human brain lipid metabolism and health remains unclear.
- Here we show that sortilin mediates neuronal uptake of polyunsaturated fatty acids carried by apolipoprotein E (apoE).
- Using humanized mouse strains and induced pluripotent stem cell-based cell models of brain lipid homeostasis, we demonstrate that internalized lipids are converted into ligands for peroxisome proliferator-activated receptor alpha inducing transcription profiles that enable neurons to use long-chain fatty acids as metabolic fuel when glucose is limited.
- This pathway works with apoE3 but cannot operate with the Alzheimer disease risk factor apoE4, which disrupts sortilin's endocytic activity.
- Our data indicate a role for the lipoprotein receptor sortilin in metabolic fuel choice in neurons, which may be crucial when glucose supply is limited, such as in the ageing brain.
Why it matters
In mouse and cell models, sortilin was shown to help neurons take up polyunsaturated fatty acids carried by apolipoprotein E, providing an alternative fuel when glucose is limited. This pathway worked with apoE3 but not with the Alzheimer risk factor apoE4, which disrupted sortilin's activity.
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Study details
- Evidence strengthLow
How this study scored 44/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Nature Metabolism) |
| Journal's citation record | 1 / 4 | Nature Metabolism: journal h-index 148 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 3 / 7 | Cited 18 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 6.0 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 4 / 6 | Cited 9.9× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 2 / 4 | Cited 18 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Thomas E. Willnow: h-index 79 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | Aarhus University: institution h-index 976 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 5 institution(s) in 3 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41102453) |
| Free to read | 2 / 2 | Free to read |
| Total | 44 / 100 | — |
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Read the original
- DOI: 10.1038/s42255-025-01389-5
- PubMed: 41102453
- Original source →
- Free full text: Nature Metabolism →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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