The role of specific dietary components on cholesterol balance and the initiation and propagation of cholesterol gallstone disease has not been clearly defined. This proposal focuses on the role of important dietary components, fiber and fat, in the regulation of cholesterol balance and changes occurring in hepatic and gallbladder bile in two animal models of cholesterol cholelithiasis, namely, the prairie dog and the hamster. It is proposed to use the prairie dog model to define the mechanisms whereby gallstones are produced by cholesterol-free diets (alfalfa/corn) and to elucidate the role of dietary fiber in this process. Sterol balance studies in animals on the alfalfa/corn diets will permit determination of lipoprotein cholesterol, cholesterol absorption and turnover, and cholesterol and bile acid synthesis. Relevant events in hepatic and gallbladder bile will be measured concurrently, for example, the vesicular to micellar ratio of biliary cholesterol, biliary bile acid composition, biliary lipids, pH, protein, bile flow, phospholipid composition, and mucin secretion. In addition to alfalfa, it is proposed to carry out experiments with other fibers, such as, oat bran, corn bran, cellulose, pectin and psyllium. [Cholestyramine will be studied for comparison.] This investigation will establish the mode of action of the different fibers on cholesterol metabolism, bile composition and cholelithiasis. The effect of dietary fat on cholesterol metabolism and gallstones will be studied in the hamster model of cholesterol cholelithiasis developed by the PI. The fats to be investigated include butterfat, olive oil, corn oil and menhaden oil. Specific attention will be paid to caloric intake of all animals. Correlations will be sought between cholesterol balance (cholesterol metabolism) and certain variables thought to be involved in gallstone formation. These include secretion rates of bile and biliary lipids, micellar and vesicular cholesterol, phospholipid molecular species, mucin secretion, and nucleation time. It is the long-term objective of this study to gain a better understanding of the role of specific dietary components, particularly fat and fiber, on biliary cholesterol cholelithiasis. It is anticipated that specific fats or fibers may either enhance or inhibit gallstone formation. The results of these animal studies can then be employed to design meaningful studies in man.
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