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Structure dynamics of ApoA-I amyloidogenic variants in small HDL increase their ability to mediate cholesterol efflux

Nilsson, Oktawia LU ; Lindvall, Mikaela ; Obici, Laura ; Ekström, Simon LU ; Lagerstedt, Jens O. LU and Del Giudice, Rita LU (2021) In Journal of Lipid Research 62.
Abstract

Apolipoprotein A-I (ApoA-I) of high density lipoproteins (HDLs) is essential for the transportation of cholesterol between peripheral tissues and the liver. However, specific mutations in ApoA-I of HDLs are responsible for a late-onset systemic amyloidosis, the pathological accumulation of protein fibrils in tissues and organs. Carriers of these mutations do not exhibit increased cardiovascular disease risk despite displaying reduced levels of ApoA-I/ HDL cholesterol. To explain this paradox, we show that the HDL particle profiles of patients carrying either L75P or L174S ApoA-I amyloidogenic variants show a higher relative abundance of the 8.4-nm versus 9.6-nm particles and that serum from patients, as well as reconstituted 8.4- and... (More)

Apolipoprotein A-I (ApoA-I) of high density lipoproteins (HDLs) is essential for the transportation of cholesterol between peripheral tissues and the liver. However, specific mutations in ApoA-I of HDLs are responsible for a late-onset systemic amyloidosis, the pathological accumulation of protein fibrils in tissues and organs. Carriers of these mutations do not exhibit increased cardiovascular disease risk despite displaying reduced levels of ApoA-I/ HDL cholesterol. To explain this paradox, we show that the HDL particle profiles of patients carrying either L75P or L174S ApoA-I amyloidogenic variants show a higher relative abundance of the 8.4-nm versus 9.6-nm particles and that serum from patients, as well as reconstituted 8.4- and 9.6-nm HDL particles (rHDL), possess increased capacity to catalyze cholesterol efflux from macrophages. Synchrotron radiation circular dichroism and hydrogendeuterium exchange revealed that the variants in 8.4-nm rHDL have altered secondary structure composition and display a more flexible binding to lipids than their native counterpart. The reduced HDL cholesterol levels of patients carrying ApoA-I amyloidogenic variants are thus balanced by higher proportion of small, dense HDL particles, and better cholesterol efflux due to altered, region-specific protein structure dynamics.

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author
; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Amyloidosis, Apolipoprotein A-I, Apolipoproteins, Cardiovascular disease, Cholesterol efflux, High density lipoprotein/HDL, Hydrogen-deuterium exchange/HDX, Protein structure
in
Journal of Lipid Research
volume
62
article number
100004
publisher
American Society for Biochemistry and Molecular Biology
external identifiers
  • pmid:33203718
  • scopus:85100681456
ISSN
0022-2275
DOI
10.1194/JLR.RA120000920
language
English
LU publication?
yes
id
424c7415-4ef1-4a65-9cf7-0e6d201d46bd
date added to LUP
2021-02-25 07:46:29
date last changed
2024-06-27 08:59:32
@article{424c7415-4ef1-4a65-9cf7-0e6d201d46bd,
  abstract     = {{<p>Apolipoprotein A-I (ApoA-I) of high density lipoproteins (HDLs) is essential for the transportation of cholesterol between peripheral tissues and the liver. However, specific mutations in ApoA-I of HDLs are responsible for a late-onset systemic amyloidosis, the pathological accumulation of protein fibrils in tissues and organs. Carriers of these mutations do not exhibit increased cardiovascular disease risk despite displaying reduced levels of ApoA-I/ HDL cholesterol. To explain this paradox, we show that the HDL particle profiles of patients carrying either L75P or L174S ApoA-I amyloidogenic variants show a higher relative abundance of the 8.4-nm versus 9.6-nm particles and that serum from patients, as well as reconstituted 8.4- and 9.6-nm HDL particles (rHDL), possess increased capacity to catalyze cholesterol efflux from macrophages. Synchrotron radiation circular dichroism and hydrogendeuterium exchange revealed that the variants in 8.4-nm rHDL have altered secondary structure composition and display a more flexible binding to lipids than their native counterpart. The reduced HDL cholesterol levels of patients carrying ApoA-I amyloidogenic variants are thus balanced by higher proportion of small, dense HDL particles, and better cholesterol efflux due to altered, region-specific protein structure dynamics. </p>}},
  author       = {{Nilsson, Oktawia and Lindvall, Mikaela and Obici, Laura and Ekström, Simon and Lagerstedt, Jens O. and Del Giudice, Rita}},
  issn         = {{0022-2275}},
  keywords     = {{Amyloidosis; Apolipoprotein A-I; Apolipoproteins; Cardiovascular disease; Cholesterol efflux; High density lipoprotein/HDL; Hydrogen-deuterium exchange/HDX; Protein structure}},
  language     = {{eng}},
  publisher    = {{American Society for Biochemistry and Molecular Biology}},
  series       = {{Journal of Lipid Research}},
  title        = {{Structure dynamics of ApoA-I amyloidogenic variants in small HDL increase their ability to mediate cholesterol efflux}},
  url          = {{http://dx.doi.org/10.1194/JLR.RA120000920}},
  doi          = {{10.1194/JLR.RA120000920}},
  volume       = {{62}},
  year         = {{2021}},
}