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Jens Lagerstedt

Associate professor

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

Author

  • Oktawia Nilsson
  • Mikaela Lindvall
  • Laura Obici
  • Simon Ekström
  • Jens O. Lagerstedt
  • Rita Del Giudice

Summary, in English

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.

Department/s

  • Medical Protein Science
  • BioMS
  • LINXS - Lund Institute of advanced Neutron and X-ray Science
  • EXODIAB: Excellence in Diabetes Research in Sweden

Publishing year

2021

Language

English

Publication/Series

Journal of Lipid Research

Volume

62

Document type

Journal article

Publisher

American Society for Biochemistry and Molecular Biology

Topic

  • Cell and Molecular Biology

Keywords

  • Amyloidosis
  • Apolipoprotein A-I
  • Apolipoproteins
  • Cardiovascular disease
  • Cholesterol efflux
  • High density lipoprotein/HDL
  • Hydrogen-deuterium exchange/HDX
  • Protein structure

Status

Published

Research group

  • Medical Protein Science
  • BioMS

ISBN/ISSN/Other

  • ISSN: 0022-2275