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

Jason A. Holt, Guizhen Luo, Andrew N. Billin, John Bisi, Y. Yvette McNeill, Karen F. Kozarsky, Mary Donahee, Da Yuan Wang, Traci A. Mansfield, Steven A. Kliewer, Bryan Goodwin, Stacey A. Jones

Research output: Contribution to journalArticle

467 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1581-1591
Number of pages11
JournalGenes and Development
Volume17
Issue number13
DOIs
StatePublished - Jul 1 2003

Keywords

  • Bile acid
  • CYP7A1
  • FXR
  • Fibroblast growth factor
  • JNK

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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    Holt, J. A., Luo, G., Billin, A. N., Bisi, J., McNeill, Y. Y., Kozarsky, K. F., Donahee, M., Wang, D. Y., Mansfield, T. A., Kliewer, S. A., Goodwin, B., & Jones, S. A. (2003). Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis. Genes and Development, 17(13), 1581-1591. https://doi.org/10.1101/gad.1083503