Abstract

Previous data from other laboratories as well as ours demonstrated that bile salts play an important role in the absorption of cholesterol by the small intestine and its role extends beyond the solubilization of cholesterol. We have also demonstrated recently in vivo that the absorption of phosphatidylcholine (PC) inhibits the absorption of cholesterol by the small intestine. Based on these initial observations, we hypothesize that: I: The uptake of cholesterol by the enterocytes is influenced by the composition and structure of the bile salt micelle; II. The uptake of cholesterol by the enterocytes is mediated by binding proteins present in the brush border membrane. To test these hypotheses, lymph fistula rats as well as in vitro preparations of the small intestinal mucosa will be used.
SPECIFIC AIM 1. Preliminary study from our laboratory demonstrated that in rats with intact enterohepatic circulation of bile slats, tauroursodeoxycholate (UDC-Tau) still inhibits the uptake of cholesterol by the rat small intestine. To gain a better understanding of the mechanism of how UDC-tau inhibits intestinal cholesterol absorption, we will determine how variations in the molar ratio of UDC-tau/taurocholate (C-tau) affects the intestinal absorption of cholesterol in bile fistula rats.
SPECIFIC AIM 2. To define how alterations in the bile in the bile acid structure affect the intestinal absorption of cholesterol, other dietary lipids, and lipid soluble vitamins in lymph fistula rats.
SPECIFIC AIM 3. We will determine which component of the phosphatidylcholine (PC) molecule is important in its inhibition of cholesterol absorption by the small intestine and how triglyceride (TG), or its digestion products, reverse this inhibition.
SPECIFIC AIM 4. We will determine if the uptake of cholesterol from mixed micelles by the enterocytes is protein-mediated and more specifically, if the inhibition of cholesterol uptake by UDC-tau is protein-mediated and is CD36 involved with this process.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK054504-04
Application #
6578769
Study Section
Project Start
2002-03-01
Project End
2003-02-28
Budget Start
Budget End
Support Year
4
Fiscal Year
2002
Total Cost
$186,685
Indirect Cost

  Institution

Name
University of Cincinnati
Department
Type
DUNS #
City
Cincinnati
State
OH
Country
United States
Zip Code
45221

  Publications

Clegg, Deborah J; Gotoh, Koro; Kemp, Christopher et al. (2011) Consumption of a high-fat diet induces central insulin resistance independent of adiposity. Physiol Behav 103:10-6
Kato, Takanobu; Choi, Youkyung; Elmowalid, Gamal et al. (2008) Hepatitis C virus JFH-1 strain infection in chimpanzees is associated with low pathogenicity and emergence of an adaptive mutation. Hepatology 48:732-40
Shen, Ling; Tso, Patrick; Woods, Stephen C et al. (2008) Brain apolipoprotein E: an important regulator of food intake in rats. Diabetes 57:2092-8
Shen, Ling; Tso, Patrick; Woods, Stephen C et al. (2007) Hypothalamic apolipoprotein A-IV is regulated by leptin. Endocrinology 148:2681-9
Wang, Yanwen; Jones, Peter J H; Woollett, Laura A et al. (2006) Effects of chenodeoxycholic acid and deoxycholic acid on cholesterol absorption and metabolism in humans. Transl Res 148:37-45
Woollett, L A; Wang, Y; Buckley, D D et al. (2006) Micellar solubilisation of cholesterol is essential for absorption in humans. Gut 55:197-204
Gotoh, Koro; Liu, Min; Benoit, Stephen C et al. (2006) Apolipoprotein A-IV interacts synergistically with melanocortins to reduce food intake. Am J Physiol Regul Integr Comp Physiol 290:R202-7
Hui, David Y; Howles, Philip N (2005) Molecular mechanisms of cholesterol absorption and transport in the intestine. Semin Cell Dev Biol 16:183-92
Demmers, Thea A; Jones, Peter J H; Wang, Yanwen et al. (2005) Effects of early cholesterol intake on cholesterol biosynthesis and plasma lipids among infants until 18 months of age. Pediatrics 115:1594-601
Tso, Patrick; Liu, Min (2004) Apolipoprotein A-IV, food intake, and obesity. Physiol Behav 83:631-43

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