Abstract
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.
Highlights
Introductionhigh density lipoprotein (HDL) particles are further modified by interaction with additional cellular receptors (ABCG1 and scavenger receptor BI (SR-BI)) and with soluble enzymes, including the lecithin-cholesteryl acyl transferase (LCAT) protein [3, 4]
Supplementary key words apolipoproteins apolipoprotein A-I amyloidosis high density lipoprotein/high density lipoproteins (HDLs) cholesterol efflux cardiovascular disease protein structure hydrogen-deuterium exchange/HDX
Serum samples from patients carrying Apolipoprotein A-I (ApoA-I) amyloidogenic variants and from unrelated control subjects were first depleted for apolipoprotein B prior to the analyses below in order to reduce potential variability in background cholesterol efflux
Summary
HDL particles are further modified by interaction with additional cellular receptors (ABCG1 and scavenger receptor BI (SR-BI)) and with soluble enzymes, including the lecithin-cholesteryl acyl transferase (LCAT) protein [3, 4] During these processes, the HDL particle grows from the initially formed discoidal pre-beta HDL species to larger, spherical HDL particles, a process that is facilitated by flexibility in the ApoA-I structure [5]. In ApoA-I variants carrying single amino acid substitutions, this flexibility might be causative for increased susceptibility to proteolytic remodeling and subsequent protein aggregation This is the case for 23 currently known human amyloidogenic variants of the APOA1 gene that lead to progressive accumulation of ApoA-I protein in the liver, heart, kidneys, larynx, skin, and/or testis [8,9,10,11,12].
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