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 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.
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Inagaki
authors.forename: Mihwa
authors.initials: M
authors.lastname: Choi
authors.forename: Antonio
authors.initials: A
authors.lastname: Moschetta
authors.forename: Li
authors.initials: L
authors.lastname: Peng
authors.forename: Carolyn L
authors.initials: CL
authors.lastname: Cummins
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: McDonald
authors.forename: Guizhen
authors.initials: G
authors.lastname: Luo
authors.forename: Stacey A
authors.initials: SA
authors.lastname: Jones
authors.forename: Bryan
authors.initials: B
authors.lastname: Goodwin
authors.forename: James A
authors.initials: JA
authors.lastname: Richardson
authors.forename: Robert D
authors.initials: RD
authors.lastname: Gerard
authors.forename: Joyce J
authors.initials: JJ
authors.lastname: Repa
authors.forename: David J
authors.initials: DJ
authors.lastname: Mangelsdorf
authors.forename: Steven A
authors.initials: SA
authors.lastname: Kliewer
mesh_terms: 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
chemical_list: 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