Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis

Takeshi Inagaki, Mihwa Choi, Antonio Moschetta, Li Peng, Carolyn L. Cummins, Jeffrey G. McDonald, Guizhen Luo, Stacey A. Jones, Bryan Goodwin, James A. Richardson, Robert D. Gerard, Joyce J. Repa, David J. Mangelsdorf, Steven A. Kliewer

Research output: Contribution to journalArticle

1031 Scopus citations

Abstract

The liver and intestine play crucial roles in maintaining bile acid homeostasis. Here, we demonstrate that fibroblast growth factor 15 (FGF15) signals from intestine to liver to repress the gene encoding cholesterol 7α-hydroxylase (CYP7A1), which catalyzes the first and rate-limiting step in the classical bile acid synthetic pathway. FGF15 expression is stimulated in the small intestine by the nuclear bile acid receptor FXR and represses Cyp7a1 in liver through a mechanism that involves FGF receptor 4 (FGFR4) and the orphan nuclear receptor SHP. Mice lacking FGF15 have increased hepatic CYP7A1 mRNA and protein levels and corresponding increases in CYP7A1 enzyme activity and fecal bile acid excretion. These studies define FGF15 and FGFR4 as components of a gut-liver signaling pathway that synergizes with SHP to regulate bile acid synthesis.

Original languageEnglish (US)
Pages (from-to)217-225
Number of pages9
JournalCell Metabolism
Volume2
Issue number4
DOIs
StatePublished - Oct 1 2005

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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