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Structural determinants in ApoA-I amyloidogenic variants explain improved cholesterol metabolism despite low HDL levels

Del Giudice, Rita LU ; Domingo-Espín, Joan LU ; Iacobucci, Ilaria ; Nilsson, Oktawia LU ; Monti, Maria Cristina ; Monti, Daria Maria and Lagerstedt, Jens O LU (2017) In Biochimica et Biophysica Acta 1863(12). p.3038-3048
Abstract

Twenty Apolipoprotein A-I (ApoA-I) variants are responsible for a systemic hereditary amyloidosis in which protein fibrils can accumulate in different organs, leading to their failure. Several ApoA-I amyloidogenic mutations are also associated with hypoalphalipoproteinemia, low ApoA-I and high-density lipoprotein (HDL)-cholesterol plasma levels; however, subjects affected by ApoA-I-related amyloidosis do not show a higher risk of cardiovascular diseases (CVD). The structural features, the lipid binding properties and the functionality of four ApoA-I amyloidogenic variants were therefore inspected in order to clarify the paradox observed in the clinical phenotype of the affected subjects. Our results show that ApoA-I amyloidogenic... (More)

Twenty Apolipoprotein A-I (ApoA-I) variants are responsible for a systemic hereditary amyloidosis in which protein fibrils can accumulate in different organs, leading to their failure. Several ApoA-I amyloidogenic mutations are also associated with hypoalphalipoproteinemia, low ApoA-I and high-density lipoprotein (HDL)-cholesterol plasma levels; however, subjects affected by ApoA-I-related amyloidosis do not show a higher risk of cardiovascular diseases (CVD). The structural features, the lipid binding properties and the functionality of four ApoA-I amyloidogenic variants were therefore inspected in order to clarify the paradox observed in the clinical phenotype of the affected subjects. Our results show that ApoA-I amyloidogenic variants are characterized by a different oligomerization pattern and that the position of the mutation in the ApoA-I sequence affects the molecular structure of the formed HDL particles. Although lipidation increases ApoA-I proteins stability, all the amyloidogenic variants analyzed show a lower affinity for lipids, both in vitro and in ex vivo mouse serum. Interestingly, the lower efficiency at forming HDL particles is compensated by a higher efficiency at catalysing cholesterol efflux from macrophages. The decreased affinity of ApoA-I amyloidogenic variants for lipids, together with the increased efficiency in the cholesterol efflux process, could explain why, despite the unfavourable lipid profile, patients affected by ApoA-I related amyloidosis do not show a higher CVD risk.

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type
Contribution to journal
publication status
published
subject
in
Biochimica et Biophysica Acta
volume
1863
issue
12
pages
11 pages
publisher
Elsevier
external identifiers
  • scopus:85032660188
  • wos:000415771000004
  • pmid:28887204
ISSN
0006-3002
DOI
10.1016/j.bbadis.2017.09.001
language
English
LU publication?
yes
id
9a8c916b-3cad-4b0d-9f9d-65ea8859893d
date added to LUP
2017-10-19 20:07:35
date last changed
2025-01-07 23:16:07
@article{9a8c916b-3cad-4b0d-9f9d-65ea8859893d,
  abstract     = {{<p>Twenty Apolipoprotein A-I (ApoA-I) variants are responsible for a systemic hereditary amyloidosis in which protein fibrils can accumulate in different organs, leading to their failure. Several ApoA-I amyloidogenic mutations are also associated with hypoalphalipoproteinemia, low ApoA-I and high-density lipoprotein (HDL)-cholesterol plasma levels; however, subjects affected by ApoA-I-related amyloidosis do not show a higher risk of cardiovascular diseases (CVD). The structural features, the lipid binding properties and the functionality of four ApoA-I amyloidogenic variants were therefore inspected in order to clarify the paradox observed in the clinical phenotype of the affected subjects. Our results show that ApoA-I amyloidogenic variants are characterized by a different oligomerization pattern and that the position of the mutation in the ApoA-I sequence affects the molecular structure of the formed HDL particles. Although lipidation increases ApoA-I proteins stability, all the amyloidogenic variants analyzed show a lower affinity for lipids, both in vitro and in ex vivo mouse serum. Interestingly, the lower efficiency at forming HDL particles is compensated by a higher efficiency at catalysing cholesterol efflux from macrophages. The decreased affinity of ApoA-I amyloidogenic variants for lipids, together with the increased efficiency in the cholesterol efflux process, could explain why, despite the unfavourable lipid profile, patients affected by ApoA-I related amyloidosis do not show a higher CVD risk.</p>}},
  author       = {{Del Giudice, Rita and Domingo-Espín, Joan and Iacobucci, Ilaria and Nilsson, Oktawia and Monti, Maria Cristina and Monti, Daria Maria and Lagerstedt, Jens O}},
  issn         = {{0006-3002}},
  language     = {{eng}},
  number       = {{12}},
  pages        = {{3038--3048}},
  publisher    = {{Elsevier}},
  series       = {{Biochimica et Biophysica Acta}},
  title        = {{Structural determinants in ApoA-I amyloidogenic variants explain improved cholesterol metabolism despite low HDL levels}},
  url          = {{http://dx.doi.org/10.1016/j.bbadis.2017.09.001}},
  doi          = {{10.1016/j.bbadis.2017.09.001}},
  volume       = {{1863}},
  year         = {{2017}},
}