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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.

Author information

1
Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, United States.
2
Department of Pharmacology, UT Southwestern Medical Center, 6001 Forest Park Rd, Dallas, TX 75390, United States.
3
Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States.
4
Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, United States. Electronic address: yangl@amgen.com.

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.

KEYWORDS:

Bile acid metabolism; FGF19; FGF21; FGFR4; βKlotho

PMID:
28041926
PMCID:
PMC5233823
DOI:
10.1016/j.ebiom.2016.12.016
[Indexed for MEDLINE]
Free PMC Article

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