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The Role of OSTalpha/beta in Bile Acid and Lipid Metabolism

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abstract
Bile acids are synthesized from cholesterol in the liver. Fecal bile acid excretion accounts for nearly half of daily cholesterol disposal. It has been known for many years that ileal resection or blocking intestinal apical absorption of bile acids induces hepatic bile acid synthesis. However, inactivation of the intestinal basolateral bile acid transporter OSTalpha-OSTbeta was associated with decreased hepatic bile acid synthesis. To further understand the underlying mechanisms responsible for this altered bile acid homeostasis, Osta-Fxr double null mice were generated and studied. Inactivation of Ostalpha was associated with significant increases in small bowel length, small bowel mass predominantly in ileum, villus width and crypt depth, and villus epithelial cell number. Fxr deficiency in Osta-/- mice reversed the increase in intestinal length, but not the increases in small bowel mass or villus hyperplasia. Fxr deficiency in Osta-/- mice was associated with decreased ileal Fgf15 mRNA expression, increased hepatic Cyp7a1 expression, increased fecal bile acid excretion, increased bile acid pool size, and restoration of intestinal cholesterol absorption. Ileal enterocyte Fgf15 mRNA expression was not significantly increased, but ileal levels of FGF15 protein was increased almost 10-fold in Osta-/- mice, and total ileal FGF15 protein levels are further elevated to 20-fold due to the increase in ileal enterocyte number.
subject
Atherosclerosis
Bile Acid
Enterohepatic Circulation
FGF15
FXR
Organic Solute Transporter
contributor
Lan, Tian (author)
Dawson, Paul A. (committee chair)
Parks, John S. (committee member)
Shelness, Gregory S. (committee member)
Brown, Jonathan Mark (committee member)
date
2013-06-06T21:19:18Z (accessioned)
2014-06-06T08:30:09Z (available)
2013 (issued)
degree
Molecular Pathology (discipline)
embargo
2014-06-06 (terms)
identifier
http://hdl.handle.net/10339/38511 (uri)
language
en (iso)
publisher
Wake Forest University
title
The Role of OSTalpha/beta in Bile Acid and Lipid Metabolism
type
Dissertation

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