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

  1. Jason A. Holt1,
  2. Guizhen Luo1,
  3. Andrew N. Billin1,
  4. John Bisi2,
  5. Y. Yvette McNeill3,
  6. Karen F. Kozarsky4,
  7. Mary Donahee4,
  8. Da Yuan Wang5,
  9. Traci A. Mansfield6,
  10. Steven A. Kliewer1,7,
  11. Bryan Goodwin1, and
  12. Stacey A. Jones1,8
  1. 1Nuclear Receptor Discovery Research, High Throughput Biology, 2Gene Interference, 3Transgenics, GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA 4Protein Agents and Human Gene Therapy, 5Protein Biochemistry, GlaxoSmithKline, King of Prussia, Pennsylvania 19406, USA 6CuraGen 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 7α-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.

Keywords

Footnotes

  • 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.

    • Accepted May 6, 2003.
    • Received February 11, 2003.
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