MECHANISMS OF BILE SALT MEDIATED CHOLESTEROL ABSORPTION

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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.