Intralumenal Effects on Cholesterol Absorption/Synthesis
Condition: Healthy
Study type: Interventional

Summary: 
      The overall goal of this study is to better understand how cholesterol is absorbed and
      utilized in the body(metabolism) and how serum cholesterol affects the development of
      hardening of the arteries (atherosclerosis). The purpose of aim 1 is to assess the role of
      the amount of different bile acids in the intestine and how they affect the absorption,
      synthesis and digestion of cholesterol. The effect that these bile acids have on how fast the
      gall bladder empties and the release of a hormone in the blood after a meal will also be
      studied. The purpose of aim 2 is to assess the role of phospholipid (a fat containing the
      element phosphorus) in the intestine and how it affects the absorption, synthesis and
      digestion of cholesterol in normal people and in people with a genetic condition (mdr3
      deficiency)that affects phospholipid and bile acid metabolism. The purpose of aim 3 is to
      assess the role of a material that acts like a detergent called Pluronic F-68 which is known
      to block the absorption of cholesterol. The purpose of aim 4 is to determine if the
      cholesterol from food and the cholesterol made by the body are digested and absorbed
      differently.
    

Detailed description: 
      Cholesterol absorption plays a key role in cholesterol homeostasis and understanding the
      lumenal events that play key roles in absorption remain poorly understood. The aims of the
      present study are fourfold: 1) To determine whether previously observed effects on
      cholesterol absorption during bile acid feeding are related to changes in pool size and
      intestinal transit or meal stimulated gall bladder emptying or plasma cholecystokinin levels.
      2) To determine the effect of dietary sphingomyelin on cholesterol absorption, micellar
      solubilization and synthesis in normal adults and to assess the effects of intralumenal
      cholesterol solubilization, absorption and synthesis in adults with heterozygous mdr 3
      deficiency (a defect leading to low biliary phospholipid content). 3) To determine the
      mechanism of action of a non-ionic detergent, Pluronic F-68, by evaluating its effect on
      cholesterol solubilization and distribution between micelles and vesicles, on cholesterol
      absorption and synthesis. 4) To evaluate the intralumenal solubilization and distribution
      within micelles and vesicles of biliary compared to dietary cholesterol in humans and assess
      the impact of ezetimibe treatment on absorption of endogenous or exogenous cholesterol by
      assessing absorption of human contents in the biliary diverted, rat lymph fistula model. For
      each of these aims, subjects will be studied while consuming well-controlled diets as
      outpatients with a combination of human and animal techniques. Techniques employed for human
      studies will include state-of-the art techniques utilizing stable isotopes and isotope ratio
      mass spectrometry, gas chromatography. Translational studies in animals will be used
      including novel techniques to measure fat absorption as well as the use of the lymph fistula
      rat model for assessment of lipid absorption and hamsters for assessment of bile acid and
      sterol synthesis. Integration of animal/human techniques will provide tools to characterize
      the role of modifications of the intralumenal environment on cholesterol solubilization and
      human cholesterol absorption and synthesis.
    

Intervention name(s): Bile Acids (Cholic, Ursodeoxycholic, Chenodeoxycholic); Sphingomyelin; C13 Stable isotope of Cholesterol
Intervention type(s): Dietary Supplement; Dietary Supplement; Other
Intervention description(s): 15 mg/kg/day for 18 days; 1000mg/day for 19 days; Food provided for 3 days and one time dose of 113mg of C13 Cholesterol.
Intervention MeSH terms: Bile Acids and Salts
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Prevention