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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK042433-01
Application #
3243500
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1990-07-01
Project End
1995-06-30
Budget Start
1990-07-01
Budget End
1991-06-30
Support Year
1
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Duane, W C; Hartich, L A; Bartman, A E et al. (2000) Diminished gene expression of ileal apical sodium bile acid transporter explains impaired absorption of bile acid in patients with hypertriglyceridemia. J Lipid Res 41:1384-9
Duane, W C; Javitt, N B (1999) 27-hydroxycholesterol: production rates in normal human subjects. J Lipid Res 40:1194-9
Duane, W C (1999) Effects of soybean protein and very low dietary cholesterol on serum lipids, biliary lipids, and fecal sterols in humans. Metabolism 48:489-94
Duane, W C (1997) Cholesterol metabolism in familial hypertriglyceridemia: effects of obesity versus triglyceride level. J Lab Clin Med 130:635-42
Duane, W C (1997) Measurement of bile acid synthesis by three different methods in hypertriglyceridemic and control subjects. J Lipid Res 38:183-8
Duane, W C (1997) Effects of legume consumption on serum cholesterol, biliary lipids, and sterol metabolism in humans. J Lipid Res 38:1120-8
Duane, W C; Schteingart, C D; Ton-Nu, H T et al. (1996) Validation of [22,23-3H]cholic acid as a stable tracer through conversion to deoxycholic acid in human subjects. J Lipid Res 37:431-6
Duane, W C (1995) Serum lathosterol levels in human subjects reflect changes in whole body cholesterol synthesis induced by lovastatin but not dietary cholesterol. J Lipid Res 36:343-8
Duane, W C (1995) Abnormal bile acid absorption in familial hypertriglyceridemia. J Lipid Res 36:96-107
Duane, W C; Gilboe, D P (1995) Measurement of bile salt aggregation equilibria using kinetic dialysis and spreadsheet modeling. Anal Biochem 229:15-9

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