Controversy has recently arisen regarding regulation of bile acid synthesis. Our preliminary studies include the novel observation that decreasing cholesterol synthesis with lovastatin strikingly lowers return of bile acid to the liver (apparently by lowering bile acid pool size), but does not change bile acid synthesis. these findings are most consistent with the unifying hypothesis that bile acid synthesis in man is regulated by two mechanisms: 1) Feedback inhibition by bile salt returning to the liver, and 2) changes in cholesterol input (dietary or biosynthetic), AND that these two mechanisms interact such that a decrease in cholesterol input increases sensitivity of the liver for feedback inhibition. Testing this hypothesis requires measurement of four critical variables: Bile acid synthesis, cholesterol synthesis, cholesterol absorption, and return of bile acid to the liver (equivalent to secretion of bile acid into bile). We plan to measure cholesterol and bile acid synthesis by fecal sterol balance, biliary lipid secretion rates by marker perfusion, and cholesterol absorption by subtracting fecal neutral sterol output from total cholesterol presented to the duodenum (dietary and biliary). Bile acid pool sizes will be measured by isotope dilution. All these measurements will be done in four sets of experimental perturbations designed to systematically alter cholesterol input (both dietary and synthetic) and return of bile acid to the liver. For each set, 10 normal human volunteers will be studied in 4 or 5 six-week periods on a metabolic ward. Set 1: a) control, b) high cholesterol diet, c) lovastatin, 40 mg bid, and d) lovastatin + high cholesterol diet. Set 2: a) control, b) cholestyramine 4 grams qid, c) lovastatin, 40 mg bid, and d) lovastatin + cholestyramine. Set 3: a) control, b) chenodeoxycholic acid, 5 mg/kg tid, c) lovastatin, 40 mg bid, d) lovastatin + chenodeoxycholic acid, e) chenodeoxycholic acid + high cholesterol diet. Set 4: a) control, b) ursodeoxycholic acid, 5 mg/kg bid, c) lovastatin, 40 mg bid, d) lovastatin + ursodeoxycholic acid. Studying the above combinations of drugs and/or high cholesterol diet, should provide an excellent test of our hypothesis versus alternative hypotheses. These studies will also fill certain important gaps in our knowledge of effects of these individual drugs and a high cholesterol diet on biliary lipid metabolism.
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