Structural Insights into High Density Lipoprotein: Old Models and New Facts

Abstract

The physiological link between circulating high density lipoprotein (HDL) levels and cardiovascular disease is well-documented, albeit its intricacies are not well-understood. An improved appreciation of HDL function and overall role in vascular health and disease requires at its foundation a better understanding of the lipoprotein's molecular structure, its formation, and its process of maturation through interactions with various plasma enzymes and cell receptors that intervene along the pathway of reverse cholesterol transport. This review focuses on summarizing recent developments in the field of lipid free apoA-I and HDL structure, with emphasis on new insights revealed by newly published nascent and spherical HDL models constructed by combining low resolution structures obtained from small angle neutron scattering (SANS) with contrast variation and geometrical constraints derived from hydrogen–deuterium exchange (HDX), crosslinking mass spectrometry, electron microscopy, Förster resonance energy transfer, and electron spin resonance. Recently published low resolution structures of nascent and spherical HDL obtained from SANS with contrast variation and isotopic labeling of apolipoprotein A-I (apoA-I) will be critically reviewed and discussed in terms of how they accommodate existing biophysical structural data from alternative approaches. The new low resolution structures revealed and also provided some answers to long standing questions concerning lipid organization and particle maturation of lipoproteins. The review will discuss the merits of newly proposed SANS based all atom models for nascent and spherical HDL, and compare them with accepted models. Finally, naturally occurring and bioengineered mutations in apoA-I, and their impact on HDL phenotype, are reviewed and discuss together with new therapeutics employed for restoring HDL function.

Effects of a purified krill oil phospholipid rich in long-chain omega-3 fatty acids on cardiovascular disease risk factors in non-human primates with naturally occurring diabetes type-2 and dyslipidemia

“…HDL-c and HDL particles, on the other hand, were increased during treatment. ApoA1, the principal apolipoprotein in HDL [30, 31], also increased although not to the same extent as HDL-c. The size of the LDL and HDL particles did not change as a result of treatment with the omega-3 rich phospholipid (Fig.…”

Specific cholesterol binding drives drastic structural alterations in Apolipoprotein A1

“…Four major configurations have been proposed in a recent review, 29 (i) Lipid-free monomeric ApoA1, (ii) Lipid-poor ApoA1 monomer, also known as pre-β HDL, (iii) Oligomeric ApoA1 in discoidal HDL (d-HDL); and (iv) Oligomeric ApoA1 in the final matured spherical HDL (s-HDL). Furthermore, there is evidence suggesting that the ApoA1 exhibits highly diverse conformations in all the above states.…”

Protein Backbone and Average Particle Dynamics in Reconstituted Discoidal and Spherical HDL Probed by Hydrogen Deuterium Exchange and Elastic Incoherent Neutron Scattering

“…Due to the difficulty in isolating homogenous HDL preparations from plasma, for years, a majority of structural studies of HDL have focused on reconstituted discoidal HDL (rHDL), which consists of two molecules of apoA-I, phospholipid, and free cholesterol [15,16]. The existing structural models of rHDL have two apoA-I chains in an anti-parallel orientation that exist either as a double belt shape around the circumference of a central lipid bilayer comprised of phospholipid and free cholesterol [15][16][17][18][19][20][21][22][23] or as a superhelical shape wrapping around a predominantly micellar lipid core [23][24][25]. Spherical HDL (sHDL), on the other hand, is the mature form of HDL that transports cholesterol back to the liver that has typically been converted into cholesteryl ester in peripheral tissues and has a lipid core made mostly of cholesteryl esters surrounded by a phospholipid monolayer in which apoA-I is embedded, the latter acting as a scaffold, offering structural integrity to the particle.…”

“…Only a few studies have addressed experimentally the structure of sHDL in detail due to its compositional heterogeneity [14,23,[26][27][28][29][30]. While some characterization studies suggest that apoA-I in reconstituted rHDL and sHDL has similar α-helical content [31] and that the overall structure of apoA-I is similar in sHDL, either reconstituted from individual constituents or isolated from human plasma [31,32], others have noted changes in particle's properties that infer the presence of structural differences between apoA-I in rHDL versus sHDL [18,24,25,30,[33][34][35][36][37].…”