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Jens Lagerstedt

Associate professor

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

Author

  • Rita Del Giudice
  • Joan Domingo-Espín
  • Ilaria Iacobucci
  • Oktawia Nilsson
  • Maria Cristina Monti
  • Daria Maria Monti
  • Jens O Lagerstedt

Summary, in English

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.

Department/s

  • Medical Protein Science
  • EXODIAB: Excellence in Diabetes Research in Sweden

Publishing year

2017

Language

English

Pages

3038-3048

Publication/Series

Biochimica et biophysica acta

Volume

1863

Issue

12

Document type

Journal article

Publisher

Elsevier

Topic

  • Medical Biotechnology

Status

Published

Research group

  • Medical Protein Science

ISBN/ISSN/Other

  • ISSN: 0006-3002