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Genes & Dev. 17 (13): 1581-1591

Copyright © 2003 by Cold Spring Harbor Laboratory Press.

RESEARCH PAPER

Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis

Jason A. Holt1, Guizhen Luo1, Andrew N. Billin1, John Bisi2, Y. Yvette McNeill3, Karen F. Kozarsky4, Mary Donahee4, Da Yuan Wang5, Traci A. Mansfield6, Steven A. Kliewer1,7, Bryan Goodwin1, and Stacey A. Jones1,8

1 Nuclear Receptor Discovery Research, High Throughput Biology, 2 Gene Interference, 3 Transgenics, GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA 4 Protein Agents and Human Gene Therapy, 5 Protein Biochemistry, GlaxoSmithKline, King of Prussia, Pennsylvania 19406, USA 6 CuraGen Corporation, New Haven, Connecticut 06511, USA

Abstract: The nuclear bile acid receptor FXR has been proposed to play a central role in the feedback repression of the gene encoding cholesterol 7{alpha}-hydroxylase (CYP7A1), the first and rate-limiting step in the biosynthesis of bile acids. We demonstrate that FXR directly regulates expression of fibroblast growth factor-19 (FGF-19), a secreted growth factor that signals through the FGFR4 cell-surface receptor tyrosine kinase. In turn, FGF-19 strongly suppresses expression of CYP7A1 in primary cultures of human hepatocytes and mouse liver through a c-Jun N-terminal kinase (JNK)-dependent pathway. This signaling cascade defines a novel mechanism for feedback repression of bile acid biosynthesis and underscores the vital role of FXR in the regulation of multiple pathways of cholesterol catabolism in the liver.

Key Words: CYP7A1 • FXR • bile acid • fibroblast growth factor • JNK

Received for publication February 11, 2003. Accepted for publication May 6, 2003.

Article published online ahead of print. Article and publication date are at http://www.genesdev.org/cgi/doi/10.1101/gad.1083503.

7 Present address: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Corresponding author.

8 E-MAIL stacey.a.jones{at}gsk.com; FAX (919) 315-6720.

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