Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
ReviewStructure of low density lipoprotein (LDL) particles: Basis for understanding molecular changes in modified LDL
Introduction
Low density lipoprotein (LDL) particles are the main carriers of cholesterol in the human circulation and are thus key players in cholesterol transfer and metabolism. Both physical and physiological characteristics have led to a common convention for defining LDL particles as lipoprotein particles within the density limits of 1.019–1.063 g/ml. Therefore, LDL forms a heterogeneous group of particles varying greatly in size, composition and structure.
During the recent decades, various biophysical methodologies such as electron microscopy, differential scanning calorimetry (DSC), nuclear magnetic resonance (NMR) spectroscopy, X-ray crystallography, circular dichroism (CD), fluorescence spectroscopy, X-ray small angle and neutron scattering techniques have been used to characterize the structure of LDL particles. Model systems, e.g., unilamellar vesicles and emulsion particles, have also been employed in order to overcome some of the difficulties faced in studies of large and compositionally complex LDL particles. Interestingly, the first three-dimensional models and atomic-level molecular dynamics simulations of apolipoprotein A-I (apoA-I) and discoidal high density lipoprotein (HDL) particles have recently become available [1], [2]. Unfortunately, however, the large size of LDL particles presently excludes the application of corresponding methodologies to resolve the structure of apoB-100 and LDL particles (apoB-100 of 4536 amino acid residues plus approximately 3000 lipid molecules in an LDL particle in contrast to two apoA-I molecules of 243 amino acid residues plus approximately 200 lipid molecules in discoidal HDL).
Current knowledge and understanding of the LDL particle structure is therefore far from trivial. Steim and co-workers gave convincing evidence in 1968 [3] for the micellar model of lipoprotein particles. In the mid 1970s the LDL surface was suggested to be a trilayer or a bilayer, the protein moiety existing in the core of the lipoprotein particle [4]. Piece by piece, however, the data have led to the development of the current picture of the spherical lipoprotein particle as an amphipathic monolayer surrounding a hydrophobic lipid core. Moreover, a biophysical model has recently been developed for micellar lipoprotein particles [5].
More specifically, LDL particles have an average diameter of 22 nm, the core consisting of about 170 triglyceride (TG) and 1600 cholesteryl ester (CE) molecules and the surface monolayer comprising about 700 phospholipid molecules and a single copy of apoB-100 [6]. In addition, the particles contain about 600 molecules of unesterified cholesterol (UC), of which about one-third is located in the core and two-thirds in the surface [7]. It should also be noted that a few percent of the TG and CE molecules penetrate toward the surface. The main phospholipid components are phosphatidylcholine (PC) (about 450 molecules/LDL particle) and sphingomyelin (SM) (about 185 molecules/LDL particle). The LDL particles also contain lysophosphatidylcholine (lyso-PC) (about 80 molecules/LDL particle) [6], phosphatidylethanolamine (PE) (about 10 molecules/LDL particle) [8], diacylglycerol (DAG) (about 7 molecules/LDL particle) [9], ceramide (CER) (about 2 molecules/LDL particle) [10] and some phosphatidylinositol [11]. In addition to lipids, LDL particles also carry lipophilic antioxidants, such as α-tocopherol (about 6 molecules/LDL particle) and minute amounts of γ-tocopherol, carotenoids, oxycarotenoids and ubiquinol-10 [6]. The particles are in a dynamic state, their structure and physical properties being dependent on their lipid composition as well as on the conformation of apoB-100.
A characteristic phenomenon of early atherogenesis is extracellular accumulation of LDL-derived lipids in the form of small lipid droplets and vesicles, which can lead to the development of atherosclerotic lesions in the arterial intima [12], [13], [14]. Modifications in the structure of native LDL that are capable of inducing aggregation and/or fusion of the particles are currently recognized to be a prerequisite for the initiation of lipid accumulation [15], [16]. Detailed knowledge of the molecular structure of LDL particles is therefore essential for understanding the pathological processes of intimal lipid accumulation, in addition to the physiology of cholesterol metabolism.
In this review we will explore the various molecular aspects that influence the structure of LDL particles. As a combination of the existing structural information on LDL particles and closely related model systems, we present new models of the structures of native and modified LDL particles. The rationale for gathering the molecular details of LDL particles into a coherent setting is twofold. Firstly, to provide a better understanding of the structural aspects of native particles, and secondly, to build a firm basis for interpreting the structural changes in variously modified LDL particles. This will enable an understanding of the molecular characteristics that determine their fate in early atherogenesis, namely aggregation and fusion.
A schematic molecular model of a native LDL particle is given in Fig. 1. The evidence for the model is discussed in detail in the following paragraphs. Moreover, the tertiary structure of apoB-100 in an LDL particle as well as schematic molecular models for various atherogenic modifications of LDL particles will also be presented and discussed.
Section snippets
Outer surface and interfacial layers
A widespread convention is to divide the LDL particle into two structurally distinct regions: core and surface. This simple division is in good accord with the micellar model and the known molecular constituents of the particles. However, experiments employing different types of probes to obtain information on the interactions between the presumed surface and core components have led to seemingly contradictory results. Thus, a coupling between the surface phospholipids and core CE and TG was
Core
The core compartment of an LDL particle is composed mainly of CE molecules and small amounts of TG and UC. Calorimetric studies and proton NMR spectroscopy have shown that the core lipids exhibit a reversible broad phase transition at around 30°C (having a width of about 20°C and a variation of as much as 10°C in the peak temperature). Thus, above the phase transition, i.e., at a physiological temperature, the core lipids exist in a liquid-like state and, below the phase transition, in a highly
ApoB-100
ApoB-100 is one of the largest monomeric proteins known, consisting of 4536 amino acid residues [64], [65], [66]. In the apolipoprotein family, apoB-100 and apoB-48 are the only nonexchangeable members. The single molecule of apoB-100 that accompanies each LDL particle therefore originates from a VLDL particle that is modified and transformed into an LDL particle in the metabolic processes in the circulation. The apoB-100 molecule must be able to adjust for the structural and compositional
Modified LDL
Numerous hydrolytic enzymes and pro-oxidative agents are present in the arterial intima. Thus, the arterial intima has been shown to contain proteases like mast cell chymase and tryptase [89], plasmin [90], matrix metalloproteinases [91], [92], [93], [94] and lysosomal proteases [95], lipases like secretory SMase [10], [96] and phospholipase A2 (PLA2) [97], [98], and cholesterol esterase (CEase) [99], [100]. Furthermore, at least myeloperoxidase and 15-lipoxygenase but also other oxidative
Concluding remarks
Current knowledge of the molecular characteristics and structural details of LDL enables understanding of important relationships between structure and function in these particles. It has become apparent that interaction preferences between the different molecular components lead to the formation of specific nanoenvironments in the particles. These nanoenvironments, are not only of structural importance, but most likely they also influence many processes of LDL metabolism. For example, by
Acknowledgements
The Wihuri Research Institute is maintained by the Jenny and Antti Wihuri Foundation. This work was supported by grants from the Academy of Finland, the Juselius Foundation, the Federation of Finnish Insurance Companies, and the Ida Montin Foundation.
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