title: Chronic Over-expression of Fibroblast Growth Factor 21 Increases Bile Acid Biosynthesis by Opposing FGF15/19 Action.
abstract: Pharmacological doses of fibroblast growth factor (FGF) 21 effectively normalize glucose, lipid and energy homeostasis in multiple animal models with many benefits translating to obese humans with type 2 diabetes. However, a role for FGF21 in the regulation of bile acid metabolism has not been reported. Herein, we demonstrate AAV-mediated FGF21 overexpression in mice increases liver expression of the key bile acid producing enzyme, Cyp7a1, resulting in an increased bile acid pool. Furthermore, in cholecystectomized mice, FGF21-mediated bile acid pool increase led to increased transit of bile acids into colon. We elucidate that the mechanism of FGF21 induced bile acid changes is mainly through antagonizing FGF15/19 function on liver βKlotho/FGFR4 receptor complex; thus inhibiting FGF15/19-mediated suppression of Cyp7a1 expression. In conclusion, these data reveal a previously unidentified role for FGF21 on bile acid metabolism and may be relevant to understand the effects of FGF21 analogs in clinical studies.
authors.affiliation: Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, United States.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, United States.
authors.forename: Jamila
authors.initials: J
authors.lastname: Gupte
authors.affiliation: Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: Gong
authors.affiliation: Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, United States.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Weiszmann
authors.affiliation: Department of Pharmacology, UT Southwestern Medical Center, 6001 Forest Park Rd, Dallas, TX 75390, United States.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States.
authors.forename: Ki Jeong
authors.initials: KJ
authors.lastname: Lee
authors.affiliation: Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States.
authors.forename: William G
authors.initials: WG
authors.lastname: Richards
authors.affiliation: Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, United States. Electronic address: yangl@amgen.com.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis*; D015415:Biomarkers; D001835:Body Weight; D002460:Cell Line; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D015870:Gene Expression; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D000090265:Klotho Proteins; D050356:Lipid Metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D011485:Protein Binding; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D001647:Bile Acids and Salts; D015415:Biomarkers; C418622:Klb protein, mouse; D008565:Membrane Proteins; C108526:fibroblast growth factor 15, mouse; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D002790:Cholesterol 7-alpha-Hydroxylase; C502772:Cyp7a1 protein, mouse; D051499:Receptor, Fibroblast Growth Factor, Type 4; D000090265:Klotho Proteins; D005947:Glucose
keywords: Bile acid metabolism; FGF19; FGF21; FGFR4; βKlotho