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Papers In Press, published online ahead of print August 24, 2007
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Laboratory of Metabolism, National Cacner Institute, Bethesda, MD 20892
Corresponding Author: fjgonz{at}helix.nih.gov
Bile acids are amphiphilic detergents synthesized in liver that are released into the small intestine to facilitate the absorption of dietary lipids. Bile acid concentrations are controlled in part by a feedback regulatory pathway whereby activation of the Farnesoid X receptor (FXR), a nuclear receptor for bile acids, represses transcription of both the CYP7A1 gene, which encodes the rate-limiting enzyme in the classic bile acid synthesis pathway, and the CYP8B1 gene, which encodes a hydroxylase required for the synthesis of cholic acid. In this study, the tissue-specific roles of FXR were examined using liver and intestine-specific FXR null models. FXR deficiency in either liver (FxrL) or intestine (FxrIE) increased the bile acid pool size. Interestingly, treatment with the FXR-selective agonist GW4064 significantly repressed CYP7A1 in FxrL mice but not FxrIE mice, demonstrating that activation of FXR in intestine but not liver is required for acute repression of CYP7A1 in liver. This intestinal-specific effect of FXR is likely mediated through induction of the hormone fibroblast growth factor 15, which suppresses CYP7A1. In comparison to CYP7A1, FXR-mediated repression of CYP8B1 was more dependent on the presence of FXR in liver and less dependent on its presence in intestine. Consistent with these findings, administration of recombinant FGF15 repressed CYP7A1 mRNA levels without significantly affecting CYP8B1 expression. Taken together, these data provide the first direct evidence that FXR-mediated repression of bile acid synthesis requires the complementary actions of FXR in both liver and intestine. Furthermore, they reveal distinct mechanistic differences in the feedback repression of CYP7A1 and CYP8B1.
Revised on August 22, 2007
Accepted on August 24, 2007
Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestine
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