Cited by 54Fibroblast Growth Factor ResearchDrug Transport and Resistance MechanismsLiver physiology and pathology

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

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Zhang, Jun, Gupte, Jamila, Gong, Yan, Weiszmann, Jennifer, Zhang, Yuan, Lee, Ki Jeong, Richards, William G., Li, Yang·2017·EBioMedicine

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.

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  • Extended exposure to elevated levels of FGF21 has been shown to increase bile acid biosynthesis by opposing the actions of FGF15/19.

    “As for the gastrointestinal issues, extended exposure to elevated levels of FGF21 has been shown to increase bile acid biosynthesis by opposing the actions of another endocrine FGF, FGF15/19 (147).”

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Authors
Zhang, J., Gupte, J., Gong, Y., Weiszmann, J., Zhang, Y., Lee, K. J., Richards, W. G., & Li, Y.
Affiliations
  • Amgen (United States) (US)
  • The University of Texas Southwestern Medical Center (US)
Corresponding author
Li, Yang
Venue
EBioMedicine
Publisher
Elsevier BV
Published
2017-02
Volume
15
Pages
173-183
ISSN
2352-3964 (ISSN-L)
OpenAlex
W2567350113
Cited by
54
References
47
Citations by year
2026: 1 · 2025: 3 · 2024: 5 · 2023: 7 · 2022: 6 · 2021: 10 · 2020: 4 · 2019: 3 · 2018: 10 · 2017: 5
FWCI
3.12
Type
journal article
Language
en
Open access
Locations
  • EBioMedicine (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Amgen
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Keywords
FGF21, bile acid synthesis, FGF15/19, CYP7A1, bile acid pool, cholecystectomy, liver, type 2 diabetes, obesity, FGF21 analogs
MeSH terms
Klotho Proteins, Animals, Bile Acids and Salts, Body Weight, Cell Line, Cholesterol 7-alpha-Hydroxylase, Fibroblast Growth Factors, Gene Expression Regulation, Glucose, Homeostasis, Membrane Proteins, Protein Binding, Signal Transduction, Biomarkers, Gene Expression, Mice, Knockout, Models, Animal, Lipid Metabolism, Mice, Receptor, Fibroblast Growth Factor, Type 4

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