Deciphering high density lipoprotein (HDL) structure-function : Detailed analysis of HDL subfractions reveals molecular differences leading to atherosclerosis risk
(2026) In International Journal of Biological Macromolecules 363.- Abstract
High-density lipoproteins (HDL) are crucial for cardiovascular health. HDL dysfunction is strongly linked to atherosclerosis and other diseases. Although HDL is often treated as a single entity, it comprises a spectrum of subfractions differing in size, structure, and composition. Understanding the ultrastructure and function of these subfractions is essential for uncovering the molecular mechanisms behind HDL dysfunction and improving disease risk prediction. We employed Small-Angle X-ray Scattering (SAXS) and cryogenic-electron tomography (cryo-ET) to analyze the structural features of total HDL and its subfractions: HDL2b, HDL2a, and HDL3. We present updated, detailed structural models showing that... (More)
High-density lipoproteins (HDL) are crucial for cardiovascular health. HDL dysfunction is strongly linked to atherosclerosis and other diseases. Although HDL is often treated as a single entity, it comprises a spectrum of subfractions differing in size, structure, and composition. Understanding the ultrastructure and function of these subfractions is essential for uncovering the molecular mechanisms behind HDL dysfunction and improving disease risk prediction. We employed Small-Angle X-ray Scattering (SAXS) and cryogenic-electron tomography (cryo-ET) to analyze the structural features of total HDL and its subfractions: HDL2b, HDL2a, and HDL3. We present updated, detailed structural models showing that the structure of HDL changes dramatically from the smallest to the largest subfraction, with HDL3 partially exposing the core to the particle's surface. Moreover, total HDL reflects the weighted sum of its subfractions, emphasizing that analysis of total HDL alone may be misleading. HDL subfractions were also studied in serum samples from 16 individuals classified as low- or high-risk for atherosclerosis. Even though biochemical differences appeared mainly in HDL2, structural differences were most pronounced in HDL3 addressing that particle composition alone cannot fully distinguish HDL dysfunction. Multimodal analysis integrating structural and biochemical data was able to separate risk groups and revealed correlations between structural parameters and cardiovascular risk status. Our findings support the importance of analyzing HDL subfractions to uncover molecular drivers of disease risk and suggest candidate biomarkers for atherosclerosis upon validation in larger cohorts.
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- author
- Correa, Yubexi ; Felderer, Birgit ; Jansen, Martin ; Gil-Carton, David ; Blanchet, Clement ; Roosen-Runge, Felix LU ; Pedersen, Jan Skov and Cárdenas, Marité LU
- organization
- publishing date
- 2026-05
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Biomedicine, Diagnostics and therapy, High-density lipoprotein, Lipid serum profile, Small-angle X-ray scattering
- in
- International Journal of Biological Macromolecules
- volume
- 363
- article number
- 152016
- publisher
- Elsevier
- external identifiers
-
- scopus:105036689908
- pmid:41991129
- ISSN
- 0141-8130
- DOI
- 10.1016/j.ijbiomac.2026.152016
- language
- English
- LU publication?
- yes
- id
- 471b206e-906b-48f3-a2c6-3ed50600f810
- date added to LUP
- 2026-05-29 14:32:32
- date last changed
- 2026-05-29 14:33:06
@article{471b206e-906b-48f3-a2c6-3ed50600f810,
abstract = {{<p>High-density lipoproteins (HDL) are crucial for cardiovascular health. HDL dysfunction is strongly linked to atherosclerosis and other diseases. Although HDL is often treated as a single entity, it comprises a spectrum of subfractions differing in size, structure, and composition. Understanding the ultrastructure and function of these subfractions is essential for uncovering the molecular mechanisms behind HDL dysfunction and improving disease risk prediction. We employed Small-Angle X-ray Scattering (SAXS) and cryogenic-electron tomography (cryo-ET) to analyze the structural features of total HDL and its subfractions: HDL<sub>2b</sub>, HDL<sub>2a</sub>, and HDL<sub>3</sub>. We present updated, detailed structural models showing that the structure of HDL changes dramatically from the smallest to the largest subfraction, with HDL<sub>3</sub> partially exposing the core to the particle's surface. Moreover, total HDL reflects the weighted sum of its subfractions, emphasizing that analysis of total HDL alone may be misleading. HDL subfractions were also studied in serum samples from 16 individuals classified as low- or high-risk for atherosclerosis. Even though biochemical differences appeared mainly in HDL<sub>2</sub>, structural differences were most pronounced in HDL<sub>3</sub> addressing that particle composition alone cannot fully distinguish HDL dysfunction. Multimodal analysis integrating structural and biochemical data was able to separate risk groups and revealed correlations between structural parameters and cardiovascular risk status. Our findings support the importance of analyzing HDL subfractions to uncover molecular drivers of disease risk and suggest candidate biomarkers for atherosclerosis upon validation in larger cohorts.</p>}},
author = {{Correa, Yubexi and Felderer, Birgit and Jansen, Martin and Gil-Carton, David and Blanchet, Clement and Roosen-Runge, Felix and Pedersen, Jan Skov and Cárdenas, Marité}},
issn = {{0141-8130}},
keywords = {{Biomedicine; Diagnostics and therapy; High-density lipoprotein; Lipid serum profile; Small-angle X-ray scattering}},
language = {{eng}},
publisher = {{Elsevier}},
series = {{International Journal of Biological Macromolecules}},
title = {{Deciphering high density lipoprotein (HDL) structure-function : Detailed analysis of HDL subfractions reveals molecular differences leading to atherosclerosis risk}},
url = {{http://dx.doi.org/10.1016/j.ijbiomac.2026.152016}},
doi = {{10.1016/j.ijbiomac.2026.152016}},
volume = {{363}},
year = {{2026}},
}