title: Bile Acids as Hormones: The FXR-FGF15/19 Pathway.
abstract: While it has long been recognized that bile acids are essential for solubilizing lipophilic nutrients in the small intestine, the discovery in 1999 that bile acids serve as ligands for the nuclear receptor farnesoid X receptor (FXR) opened the floodgates in terms of characterizing their actions as selective signaling molecules. Bile acids act on FXR in ileal enterocytes to induce the expression of fibroblast growth factor (FGF)15/19, an atypical FGF that functions as a hormone. FGF15/19 subsequently acts on a cell surface receptor complex in hepatocytes to repress bile acid synthesis and gluconeogenesis, and to stimulate glycogen and protein synthesis. FGF15/19 also stimulates gallbladder filling. Thus, the bile acid-FXR-FGF15/19 signaling pathway regulates diverse aspects of the postprandial enterohepatic response. Pharmacologically, this endocrine pathway provides exciting new opportunities for treating metabolic disease and bile acid-related disorders such as primary biliary cirrhosis and bile acid diarrhea. Both FXR agonists and FGF19 analogs are currently in clinical trials.
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Tex., USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Kliewer
authors.forename: David J
authors.initials: DJ
authors.lastname: Mangelsdorf
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics; D020895:Enterocytes / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D005943:Gluconeogenesis; D006003:Glycogen / Q000096:biosynthesis; D006706:Homeostasis; D006801:Humans; D007333:Insulin Resistance; D050356:Lipid Metabolism; D051379:Mice; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D002790:Cholesterol 7-alpha-Hydroxylase; D005346:Fibroblast Growth Factors; D006003:Glycogen; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C117476:FGF19 protein, human; C108526:fibroblast growth factor 15, mouse; C099713:nuclear receptor subfamily 0, group B, member 2; C502772:Cyp7a1 protein, mouse