Human low density lipoprotein: the mystery of core lipid packing

Abstract

LDL particles are very fascinating macromolecular assemblies of apolipoprotein B-100 and lipids and their structural features have attracted the attention of scientists for decades. There is a general consensus in the literature that LDL particles are organized into two major compartments, namely an apolar lipid core, comprised primarily of cholesteryl esters, triglycerides, and some free unesterifi ed cholesterol and an outer amphipathic shell that surrounds the apolar core. This outer shell is composed of a phospholipid monolayer containing most of the free unesterifi ed cholesterol and one single copy of apolipoprotein B-100 [for review, see Ref. ( 1 )]. LDLs are highly heterogeneous in nature, varying in buoyant density, size, surface charge, and chemical composition ( 2 ). These intrinsic properties are intimately related to intravascular metabolism of LDL ( 3 ), atherogenicity ( 4 ), and the fate of the particle in the subendothelial space ( 5 ).Of all circulating macromolecules in blood, LDLs are the only ones presently known to undergo a structural transition strikingly close to physiological temperature. Despite the identifi cation of this reversible temperature-induced transition of apolar core lipids in LDL by Deckelbaum et al. ( 6 ) in the mid-1970s, the physiological role of this transition remains elusive. Most likely, the transition might play a role in the early progression of atherosclerosis through its effects on cellular pathways of LDL recognition. In view of this, many efforts have been made to clarify the molecular details and to establish structural models for this transition in terms of geometrical constraints and chemical lipid compositions.There is broad scientifi c consensus that the core-located lipids are arranged in an ordered liquid-crystalline phase below the phase transition temperature. Above the transition temperature, however, the neutral lipids are organized in a fl uid, oil-like, disordered state as demonstrated by early X-ray and neutron scattering studies ( 7 , 8 ). The actual transition temperature of the core lipids varies between extremes of 15 and 35°C depending on the individual LDL particle. This value correlates well with the ratio of cholesteryl esters to triglycerides, being lower for higher triglyceride levels ( 6 , 7 ).Earlier structural models for LDL were principally based on an overall spherical particle shape with diameters in a size range from 18 to 25 nm. In these models, the internal core structure below the transition temperature was basically defi ned as a concentric spherical shell arrangement of cholesteryl esters. Variations within these models have been discussed on the basis of small angle X-ray scattering (SAXS) and neutron scattering experiments, and electron microscopic data ( 9 , 10 ). Later on, cryo-electron microscopy (EM) studies suggested that snap-frozen LDL, with the core lipids already in the liquid-crystalline state, exhibit an oblate ellipsoid or discoidal overall particle shape ( 11 , 12 ). Unexpectedly, in these cryo-images, the in...

Molecular anatomy of ascending aorta in atherosclerosis by MS Imaging: Specific lipid and protein patterns reflect pathology

“…In advanced lesions, necrosis of macrophages and VSMCs forms a protective fibrous cap surrounding a lipid-rich core. The LDL present in the lipid core are mainly composed of cholestearyl esters and TG in an apolar core [39,40], and surrounded by a polar monolayer of phospholipids in the surface [41]. According to the MALDI-MSI data shown here, TG, glycerophospholipids (PA) and sphingolipids (SM and PE-Cer) are located in calcified regions ( Figure 1).…”

Effect of Oxidation on the Structure of Human Low- and High-Density Lipoproteins

“…For example, SAXS results for measurements of in vitro oxLDL particles showed no major structural changes in samples oxidized with copper for <25 h (23). Over the past 40 years, knowledge about lipoprotein structure has expanded considerably, but several questions about cholesterol packing in the inner region of LDL particles and the conformational orientation of apolipoproteins remain (24)(25)(26). Recent studies with cryomicroscopy point to a lamellar organization of cholesterol in the inner region of LDL particles and to the influence of triglycerides on the temperature at which the transition from this lamellar phase to a disorganized one occurs (27).…”

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

“…The comparison of rHDL and rsHDL dynamics, as determined by EINS (rHDL vs. rsHDL in Figure 1) with two other plasma lipoproteins previously studied using EINS:VLDL vs. LDL (Figure 1 in [5]), revealed that VLDL and rHDL (the bigger lipoprotein particles in the two pairs) were softer and more flexible than LDL and rsHDL at ambient temperature, respectively. During VLDL maturation into LDL, the more dynamic triglycerides were removed, and the more rigid cholesteryl esters were incorporated, leading to apoB100 protein rearrangement and particle shrinking (e.g., from~50 nm to~20 nm [73,74]). Similarly, rsHDL particle was smaller and more compact than rHDL (8.3 vs. 9.6 nm, respectively), was rich in cholesteryl esters, and had more protein content (apoA-I or apoA-II).…”