Current evidence indicates that the very first step in the formation of cholesterol gallstone is nucleation of cholesterol from an aqueous phase (bile) into a solid crystalline phase (cholesterol monohydrate crystals). It is now realized that cholesterol, lipid with extremely poor water solubility, is solubilized in bile in two different forms - micelles of bile salts, phospholipids and cholesterol, and vesicles of phospholipids and cholesterol. Moreover, vesicular cholesterol is the component of cholesterol which is responsible for nucleation. This finding will significantly modify thinking about both the definition of """"""""cholesterol supersaturation"""""""" as well as the mechanism of biliary cholesterol secretion and solubilization. The factors controlling the dynamic interchange between the two different forms of cholesterol solubilization and the factors leading to the nucleation and precipitation of cholesterol remain unresolved. The present experiments are designed to address these issues. Prairie dogs fed cholesterol rapidly form cholesterol gallstones. This model is recognized to be, and is accepted as, an excellent model of experimental cholelithiasis. Using this model, cholesterol in bile will be separated into the micellar and vesicular forms by column chromatography and further characterized by quasi-elastic light scattering spectroscopy (QLS) to determine the size distribution of micellar and vesicular cholesterol. The quantity of biliary cholesterol and the proportion of micellar vesicular cholesterol will also be determined as a function of dietary cholesterol loading and hepatic bile salt secretory rate. Because of the new insight offered by the vesicular mode of cholesterol transport, the phase boundary and equilibria of bile salt-phospholipid-cholesterol systems will have to be extended beyond the mixed micellar tri-ordinates. Model bile systems will be used to define the phase boundaries of micelles and vesicles. QLS and small angle neutron scattering (SANS) will be used to characterize mixed micelles, vesicles, and to document the kinetics of interchange between them. Gallstones are a common problem; the affliction involves approximately 10% of men and 20% of women in the age group 55-64. The magnitude of the problem will only increase as the population ages. The results of the proposed study will yield new and important information that will lead to a better understanding of the information of gallstones, and also have an important impact on its treatment and prevention.
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