Journal
JOURNAL OF LIPID RESEARCH
Volume 62, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1194/j.jlr.RA120000920
Keywords
apolipoproteins; apolipoprotein A-I; amyloidosis; high density lipoprotein/HDL; cholesterol efflux; cardiovascular disease; protein structure; hydrogen-deuterium exchange/HDX
Categories
Funding
- Swedish Research Council [K2014-54X-22426-01-3, 2009-1039]
- Vinnova (Sweden's Innovation Agency) [2015-01549]
- Krapperup Foundation
- Crafoord Foundation
- Carl Tesdorpfs Foundation
- Royal Physiographic Society in Lund
- Sten K Johnson's Foundation
- Swedish Foundation for Strategic Research [IRC15-0067]
- project CALIPSOplus under EU Framework Programme for Research and Innovation HORIZON 2020 [730872]
- Vinnova [2015-01549] Funding Source: Vinnova
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Patients carrying ApoA-I amyloidogenic variants have a higher proportion of small, dense HDL particles, and enhanced cholesterol efflux capabilities due to altered protein structure dynamics.
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 hydrogen-deuterium 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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