Preliminary work done on human beings and experimental animals has indicated that certain forms of therapy used to treat atherosclerosis may result in enhanced formation of cholesterol gallstones. From the work of Osuga and Portman (25), and from studies at this institution (17), the squirrel monkey (Saimiri sciureus) has been shown to be an excellent animal model for the study of cholelithiasis. Cholesterol gallstones are produced with high frequency in this species when they consume a diet which contains cholesterol. It is also established that the course of the disease in these animals can be influenced by the nature of dietary fat, and by the physical activity of the animal. We propose to utilize this useful model in studies in which we will investigate the influence, on gallstone disease, of certain therapeutic modalities related to the lowering of plasma lipids. In addition to studies on the effects of dietary fat and exercise, by using animals of known parentage from our colony, we will attempt to evaluate the role of genetic factors, and of sex. In the experiments described, we will employ techniques already developed in our laboratories to evaluate simultaneously whole body sterol balance, as well as biliary lipid composition and bile acid kinetics - i.e., measurement of turnover rates and pool sizes. These studies will be done while the animals are being manipulated in the sense of altered diets, treatment with drugs, or being allowed to exercise vigorously. Finally, in collaboration with investigators in our Department of Medicine, we plan to extend some of the observations to studies on human beings. The undersigned agrees to accept responsibility for the scientific and technical conduct of the project and for provision of required progress reports if a grant is awarded as a result of this application.