Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis.
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 7alpha-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.
Inagaki
Takeshi
T
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Choi
Mihwa
M
Moschetta
Antonio
A
Peng
Li
L
Cummins
Carolyn L
CL
McDonald
Jeffrey G
JG
Luo
Guizhen
G
Jones
Stacey A
SA
Goodwin
Bryan
B
Richardson
James A
JA
Gerard
Robert D
RD
Repa
Joyce J
JJ
Mangelsdorf
David J
DJ
Kliewer
Steven A
SA
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D018938:Caco-2 Cells; D002790:Cholesterol 7-alpha-Hydroxylase / Q000096:biosynthesis; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins / Q000378:metabolism; D004764:Enterohepatic Circulation / Q000187:drug effects / Q000502:physiology*; D004848:Epithelium / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D020869:Gene Expression Profiling; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
D001647:Bile Acids and Salts; D002790:Cholesterol 7-alpha-Hydroxylase; D004268:DNA-Binding Proteins; D005346:Fibroblast Growth Factors; D012333:RNA, Messenger; D051499:Receptor, Fibroblast Growth Factor, Type 4; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C108526:fibroblast growth factor 15, mouse; C099713:nuclear receptor subfamily 0, group B, member 2; C502772:Cyp7a1 protein, mouse