Intralumenal Effects on Cholesterol Absorption/Synthesis

Study Overview
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Brief Summary
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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
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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.

Official Title
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Intralumenal Effects on Cholesterol Absorption/Synthesis

Conditions
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Healthy

Intervention / Treatment
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* Dietary Supplement: Bile Acids (Cholic, Ursodeoxycholic, Chenodeoxycholic)
* Dietary Supplement: Sphingomyelin
* Other: C13 Stable isotope of Cholesterol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Serum Total Cholesterol <200 mg/dl, LDL-Cholesterol <120 mg/dl Apo E-3/3, Apo A IV-1/1 genotypes Exclusion Criteria: Pregnancy Diabetes mellitus, other gastrointestinal, liver, kidney or heart disease Allergy to soy products

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bile Acid<br>To assess the role of bile acid pool size changes on cholesterol absorption, synthesis and intralumenal cholesterol solubilization. | Dietary Supplement: Bile Acids (Cholic, Ursodeoxycholic, Chenodeoxycholic)<br>* 15 mg/kg/day for 18 days<br>|
| Experimental: Cholesterol Absorption<br>To determine whether cholesterol absorption, synthesis and solubilization will be significantly altered by changes in phospholipid content, specifically sphingolipids and phosphatidylcholine in the intestinal lumen. | Dietary Supplement: Sphingomyelin<br>* 1000mg/day for 19 days<br>|
| Experimental: Intralumenal<br>To assess intralumenal solubilization and absorption of biliary and dietary cholesterol. | Dietary Supplement: Bile Acids (Cholic, Ursodeoxycholic, Chenodeoxycholic)<br>* 15 mg/kg/day for 18 days<br>Other: C13 Stable isotope of Cholesterol<br>* Food provided for 3 days and one time dose of 113mg of C13 Cholesterol.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary outcomes for this study are to better understand the molecular and cellular mechanisms of cholesterol metabolism and absorption. |  | 5 yrs |