The human low-density lipoprotein (LDL) has a hydrophobic core that contains mainly cholesteryl esters. These cholesteryl esters are normally in a disordered, liquid state at physiological temperature, in a more ordered, liquid-crystalline state at room temperature. However, non- human primate studies have shown that diets with a high content of cholesterol and saturated fat can generate LDL particles that have a liquid-crystalline core in vivo. It has been suggested that these abnormal LDL particles with a liquid core. The long-term goal of this study is to determine how the structure and atherogenicity of LDL are affected by the physical state of the lipoprotein core. Preliminary cryo-electron microscopic studies suggest that human LDL has a spherical shape when its cholesteryl ester core is in the liquid state, and an oblate ellipsoid, or """"""""discoid"""""""" shape when its core is in the liquid crystalline state. It is further suggested that apo B in discoid LDL has an altered conformation. These observations indicate that the alleged increase in the atherogenicity of LDL particles with a liquid-crystalline core may result from dramatic changes in the shape and substructure of the lipoprotein complex.
The specific aims of this study are: [1] To determine if changes in the physical state of the LDL core indeed to predictable changes in the shape and substructure of the lipoprotein particle. [2] To determine if LDL particles with a liquid-crystalline core differ from LDL particles with a liquid core in their affinity for the LDL receptor, in their affinity for glycosaminoglycans, or in their affinity for the macrophage scavenger receptor. It is anticipated that this study will correlate diet- inducible aberrations in the structure of LDL with significant increases in the atherogenic potential of the lipoprotein complex. The results of this project may, therefore, provide a new framework for future studies on the role of LDL particles with a liquid-crystalline core as a risk factor in coronary heart disease and stroke.
