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EBioMedicine. 2017 Feb;15:173-183. doi: 10.1016/j.ebiom.2016.12.016. Epub 2016 Dec 24.

Chronic Over-expression of Fibroblast Growth Factor 21 Increases Bile Acid Biosynthesis by Opposing FGF15/19 Action.

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Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, United States.
Department of Pharmacology, UT Southwestern Medical Center, 6001 Forest Park Rd, Dallas, TX 75390, United States.
Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States.
Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, United States. Electronic address:


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.


Bile acid metabolism; FGF19; FGF21; FGFR4; βKlotho

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