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J. Biol. Chem. 285 (19): 14486-14494

© 2010 by The American Society for Biochemistry and Molecular Biology, Inc.

Regulation of Bile Acid Synthesis by Fat-soluble Vitamins A and D*Formula

Daniel R. Schmidt{ddagger}, Sam R. Holmstrom{ddagger}§, Klementina Fon Tacer{ddagger}§1, Angie L. Bookout{ddagger}, Steven A. Kliewer{ddagger}§2, , and David J. Mangelsdorf{ddagger}3

From the {ddagger}Department of Pharmacology and Howard Hughes Medical Institute and
the §Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9050

ABSTRACT Back to Top

Abstract: Bile acids are required for proper absorption of dietary lipids, including fat-soluble vitamins. Here, we show that the dietary vitamins A and D inhibit bile acid synthesis by repressing hepatic expression of the rate-limiting enzyme CYP7A1. Receptors for vitamin A and D induced expression of Fgf15, an intestine-derived hormone that acts on liver to inhibit Cyp7a1. These effects were mediated through distinct cis-acting response elements in the promoter and intron of Fgf15. Interestingly, transactivation of both response elements appears to be required to maintain basal Fgf15 expression levels in vivo. Furthermore, whereas induction of Fgf15 by vitamin D is mediated through its receptor, the induction of Fgf15 by vitamin A is mediated through the retinoid X receptor/farnesoid X receptor heterodimer and is independent of bile acids, suggesting that this heterodimer functions as a distinct dietary vitamin A sensor. Notably, vitamin A treatment reversed the effects of the bile acid sequestrant cholestyramine on Fgf15, Shp, and Cyp7a1 expression, suggesting a potential therapeutic benefit of vitamin A under conditions of bile acid malabsorption. These results reveal an unexpected link between the intake of fat-soluble vitamins A and D and bile acid metabolism, which may have evolved as a means for these dietary vitamins to regulate their own absorption.

Key Words: Bile Acid • Intestine • Liver • Nuclear Receptors • Vitamin A • Vitamin D • FGF15 • FXR • RXR • VDR

Received for publication February 19, 2010. Revision received March 11, 2010.

FOOTNOTES Back to Top

1 Present address: Inst. of Biochemistry, Faculty of Medicine, University of Ljubljana, Zaloska 4, SI-1000 Ljubljana, Slovenia.

Author's Choice—Final version full access.

Creative Commons Attribution Non-Commercial License applies to Author Choice Articles

2 To whom correspondence may be addressed. E-mail: steven.kliewer{at}utsouthwestern.edu.

3 To whom correspondence may be addressed: University of Texas Southwestern Medical Center, 6001 Forest Park Rd., Dallas, TX 75390-9050. Tel.: 214-645-5957; Fax: 214-645-5969; E-mail: davo.mango{at}utsouthwestern.edu.

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