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

953 Citations (Scopus)

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 2005

Fingerprint

Fibroblast Growth Factors
Bile Acids and Salts
Homeostasis
Fibroblast Growth Factor Receptors
Liver
Intestines
Cholesterol 7-alpha-Hydroxylase
Small Intestine
Messenger RNA
Enzymes
Genes
Proteins

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Physiology

Cite this

Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. / Inagaki, Takeshi; Choi, Mihwa; Moschetta, Antonio; Peng, Li; Cummins, Carolyn L.; McDonald, Jeffrey G.; Luo, Guizhen; Jones, Stacey A.; Goodwin, Bryan; Richardson, James A.; Gerard, Robert D.; Repa, Joyce J.; Mangelsdorf, David J.; Kliewer, Steven A.

In: Cell Metabolism, Vol. 2, No. 4, 10.2005, p. 217-225.

Research output: Contribution to journalArticle

Inagaki, Takeshi ; Choi, Mihwa ; Moschetta, Antonio ; Peng, Li ; Cummins, Carolyn L. ; McDonald, Jeffrey G. ; Luo, Guizhen ; Jones, Stacey A. ; Goodwin, Bryan ; Richardson, James A. ; Gerard, Robert D. ; Repa, Joyce J. ; Mangelsdorf, David J. ; Kliewer, Steven A. / Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. In: Cell Metabolism. 2005 ; Vol. 2, No. 4. pp. 217-225.
@article{d18b6442ee304772bd2d285bfeb9a089,
title = "Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis",
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.",
author = "Takeshi Inagaki and Mihwa Choi and Antonio Moschetta and Li Peng and Cummins, {Carolyn L.} and McDonald, {Jeffrey G.} and Guizhen Luo and Jones, {Stacey A.} and Bryan Goodwin and Richardson, {James A.} and Gerard, {Robert D.} and Repa, {Joyce J.} and Mangelsdorf, {David J.} and Kliewer, {Steven A.}",
year = "2005",
month = "10",
doi = "10.1016/j.cmet.2005.09.001",
language = "English (US)",
volume = "2",
pages = "217--225",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "4",

}

TY - JOUR

T1 - Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis

AU - Inagaki, Takeshi

AU - Choi, Mihwa

AU - Moschetta, Antonio

AU - Peng, Li

AU - Cummins, Carolyn L.

AU - McDonald, Jeffrey G.

AU - Luo, Guizhen

AU - Jones, Stacey A.

AU - Goodwin, Bryan

AU - Richardson, James A.

AU - Gerard, Robert D.

AU - Repa, Joyce J.

AU - Mangelsdorf, David J.

AU - Kliewer, Steven A.

PY - 2005/10

Y1 - 2005/10

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=27844546989&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=27844546989&partnerID=8YFLogxK

U2 - 10.1016/j.cmet.2005.09.001

DO - 10.1016/j.cmet.2005.09.001

M3 - Article

VL - 2

SP - 217

EP - 225

JO - Cell Metabolism

JF - Cell Metabolism

SN - 1550-4131

IS - 4

ER -