Chronic Over-expression of Fibroblast Growth Factor 21 Increases Bile Acid Biosynthesis by Opposing FGF15/19 Action
Open accessAbstract
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).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [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)
- PMC
- PMC5233823
- 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
- gold
- doi.org
- Licence
- 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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