
Jens Lagerstedt
Associate professor

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