The structural organization of the neutral lipid core in human low density lipoproteins (LDL) was investigated in physicochemically defined, distinct human LDL subspecies in the density range of 1.0244 -1.0435 g/ml by evaluation of the core lipid transition temperature, chemical composition, and the behavior of spin-labeled core lipids. Calorimetric studies were performed on more than 60 LDL preparations, and the transition temperature, which varied between 19 and 32°C, was correlated to the chemical composition and revealed a discontinuity at a critical cholesteryl ester to triglyceride ratio of approximately 7:1. For electron spin resonance studies, several LDL preparations were probed with spin-labeled cholesteryl esters and triglycerides, respectively. In LDL with a high triglyceride content, both labels exhibited similar mobility behavior. In contrast, in LDL with only small concentrations of triglycerides, the behavior of labeled cholesteryl esters and labeled triglycerides differed distinctly. The cholesteryl esters were strongly immobilized below the transition temperature, whereas the triglycerides remained fluid throughout the measured temperatures. These results suggest that the critical cholesteryl ester to triglyceride mass ratio of 7:1 corresponds to two concentric compartments with a radial ratio of 2:1, where the liquid triglycerides occupy the core, and the cholesteryl esters form the frozen shell. At higher triglyceride contents, the triglyceride molecules insert into the cholesteryl ester shell and depress the peak transition temperature of the LDL core, whereas at lower triglyceride contents, excess cholesteryl esters are dissolved in the core. Low density lipoproteins (LDL)1 are the major carriers of cholesterol in the circulation and are intimately involved in atherogenesis (1 and references therein). These particles represent complex supramolecular assemblies of phospholipids (ϳ20% of the total mass), free (ϳ12%) and esterified (ϳ40%) cholesterol, triglycerides (ϳ5-10%), and a single copy of apolipoprotein B-100, a glycoprotein of 4,536 amino acids (2-4). In addition, LDL transports minor amounts of lipophilic vitamins and drugs (5). The structure of LDL can be described, in general terms, by a quasispherical core-shell model, in which the apolar constituents (cholesteryl esters (CE) and triglycerides (TG)) form a hydrophobic core of about 150 Å diameter, whereas the phospholipids, most of the unesterified cholesterol, and the apoprotein form an outer surface monolayer with a thickness of about 30 Å (6 -8).In this general sense, LDL would appear to fit readily into the structural core-shell scheme of circulating lipoproteins (9). However, LDL exhibits a distinct physical feature that makes it unique among all structural elements of blood: it is the only component to undergo a major structural transition just below physiological body temperature, in the range between 15 and 32°C (10, 11). The transition temperature varies among individual donors and is correlated to the core lipid compositi...

BackgroundThe potential physiological significance of the nanophase transition of neutral lipids in the core of low density lipoprotein (LDL) particles is dependent on whether the rate is fast enough to integrate small (±2°C) temperature changes in the blood circulation.Methodology/Principal FindingsUsing sub-second, time-resolved small-angle X-ray scattering technology with synchrotron radiation, we have monitored the dynamics of structural changes within LDL, which were triggered by temperature-jumps and -drops, respectively. Our findings reveal that the melting transition is complete within less than 10 milliseconds. The freezing transition proceeds slowly with a half-time of approximately two seconds. Thus, the time period over which LDL particles reside in cooler regions of the body readily facilitates structural reorientation of the apolar core lipids.Conclusions/SignificanceLow density lipoproteins, the biological nanoparticles responsible for the transport of cholesterol in blood, are shown to act as intrinsic nano-thermometers, which can follow the periodic temperature changes during blood circulation. Our results demonstrate that the lipid core in LDL changes from a liquid crystalline to an oily state within fractions of seconds. This may, through the coupling to the protein structure of LDL, have important repercussions on current theories of the role of LDL in the pathogenesis of atherosclerosis.

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