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Modeling Small-Angle X-ray Scattering Data for Low-Density Lipoproteins : Insights into the Fatty Core Packing and Phase Transition

Maric, Selma LU ; Lind, Tania Kjellerup LU ; Lyngsø, Jeppe ; Cárdenas, Marité LU and Pedersen, Jan Skov (2017) In ACS Nano 11(1). p.1080-1090
Abstract

Atherosclerosis and its clinical consequences are the leading cause of death in the western hemisphere. While many studies throughout the last decades have aimed at understanding the disease, the clinical markers in use today still fail to accurately predict the risks. The role of the current main clinical indicator, low density lipoprotein (LDL), in depositing fat to the vessel wall is believed to be the onset of the process. However, many subfractions of the LDL, which differ both in structure and composition, are present in the blood and among different individuals. Understanding the relationship between LDL structure and composition is key to unravel the specific role of various LDL components in the development and/or prevention of... (More)

Atherosclerosis and its clinical consequences are the leading cause of death in the western hemisphere. While many studies throughout the last decades have aimed at understanding the disease, the clinical markers in use today still fail to accurately predict the risks. The role of the current main clinical indicator, low density lipoprotein (LDL), in depositing fat to the vessel wall is believed to be the onset of the process. However, many subfractions of the LDL, which differ both in structure and composition, are present in the blood and among different individuals. Understanding the relationship between LDL structure and composition is key to unravel the specific role of various LDL components in the development and/or prevention of atherosclerosis. Here, we describe a model for analyzing small-angle X-ray scattering data for rapid and robust structure determination for the LDL. The model not only gives the overall structure but also the particular internal layering of the fats inside the LDL core. Thus, the melting of the LDL can be followed in situ as a function of temperature for samples extracted from healthy human patients and purified using a double protocol based on ultracentrifugation and size-exclusion chromatography. The model provides information on: (i) the particle-specific melting temperature of the core lipids, (ii) the structural organization of the core fats inside the LDL, (iii) the overall shape of the particle, and (iv) the flexibility and overall conformation of the outer protein/hydrophilic layer at a given temperature as governed by the organization of the core. The advantage of this method over other techniques such as cryo-TEM is the possibility of in situ experiments under near-physiological conditions which can be performed relatively fast (minutes at home source, seconds at synchrotron). This approach now allows the monitoring of structural changes in the LDL upon different stresses from the environment, such as changes in temperature, oxidation, or external agents used or currently in development against atherosclerotic plaque build-up and which are targeting the LDL.

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author
; ; ; and
publishing date
type
Contribution to journal
publication status
published
in
ACS Nano
volume
11
issue
1
pages
11 pages
publisher
The American Chemical Society (ACS)
external identifiers
  • scopus:85018478662
  • pmid:28048943
ISSN
1936-086X
DOI
10.1021/acsnano.6b08089
language
English
LU publication?
no
id
0d9ed53c-a661-4d1c-888c-9230d15821ae
date added to LUP
2018-07-19 11:59:35
date last changed
2021-04-06 04:09:10
@article{0d9ed53c-a661-4d1c-888c-9230d15821ae,
  abstract     = {<p>Atherosclerosis and its clinical consequences are the leading cause of death in the western hemisphere. While many studies throughout the last decades have aimed at understanding the disease, the clinical markers in use today still fail to accurately predict the risks. The role of the current main clinical indicator, low density lipoprotein (LDL), in depositing fat to the vessel wall is believed to be the onset of the process. However, many subfractions of the LDL, which differ both in structure and composition, are present in the blood and among different individuals. Understanding the relationship between LDL structure and composition is key to unravel the specific role of various LDL components in the development and/or prevention of atherosclerosis. Here, we describe a model for analyzing small-angle X-ray scattering data for rapid and robust structure determination for the LDL. The model not only gives the overall structure but also the particular internal layering of the fats inside the LDL core. Thus, the melting of the LDL can be followed in situ as a function of temperature for samples extracted from healthy human patients and purified using a double protocol based on ultracentrifugation and size-exclusion chromatography. The model provides information on: (i) the particle-specific melting temperature of the core lipids, (ii) the structural organization of the core fats inside the LDL, (iii) the overall shape of the particle, and (iv) the flexibility and overall conformation of the outer protein/hydrophilic layer at a given temperature as governed by the organization of the core. The advantage of this method over other techniques such as cryo-TEM is the possibility of in situ experiments under near-physiological conditions which can be performed relatively fast (minutes at home source, seconds at synchrotron). This approach now allows the monitoring of structural changes in the LDL upon different stresses from the environment, such as changes in temperature, oxidation, or external agents used or currently in development against atherosclerotic plaque build-up and which are targeting the LDL.</p>},
  author       = {Maric, Selma and Lind, Tania Kjellerup and Lyngsø, Jeppe and Cárdenas, Marité and Pedersen, Jan Skov},
  issn         = {1936-086X},
  language     = {eng},
  month        = {01},
  number       = {1},
  pages        = {1080--1090},
  publisher    = {The American Chemical Society (ACS)},
  series       = {ACS Nano},
  title        = {Modeling Small-Angle X-ray Scattering Data for Low-Density Lipoproteins : Insights into the Fatty Core Packing and Phase Transition},
  url          = {http://dx.doi.org/10.1021/acsnano.6b08089},
  doi          = {10.1021/acsnano.6b08089},
  volume       = {11},
  year         = {2017},
}