Bile Acids as Hormones: The FXR-FGF15/19 Pathway
Open accessAbstract
While it has long been recognized that bile acids are essential for solubilizing lipophilic nutrients in the small intestine, the discovery in 1999 that bile acids serve as ligands for the nuclear receptor farnesoid X receptor (FXR) opened the floodgates in terms of characterizing their actions as selective signaling molecules. Bile acids act on FXR in ileal enterocytes to induce the expression of fibroblast growth factor (FGF)15/19, an atypical FGF that functions as a hormone. FGF15/19 subsequently acts on a cell surface receptor complex in hepatocytes to repress bile acid synthesis and gluconeogenesis, and to stimulate glycogen and protein synthesis. FGF15/19 also stimulates gallbladder filling. Thus, the bile acid-FXR-FGF15/19 signaling pathway regulates diverse aspects of the postprandial enterohepatic response. Pharmacologically, this endocrine pathway provides exciting new opportunities for treating metabolic disease and bile acid-related disorders such as primary biliary cirrhosis and bile acid diarrhea. Both FXR agonists and FGF19 analogs are currently in clinical trials.
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FGF19 mimics the effect of insulin on glycogen synthesis and gluconeogenesis.
“FGF19 has the potential to regulate several pathways involved in NASH pathogenesis since it can act on CYP7A1, the rate limiting enzyme in BA synthesis from cholesterol, in addition to mimicking the effect of insulin on glycogen synthesis and gluconeogenesis [258].”
From Gut-pancreas-liver Axis as a target for treatment of NAFLD/NASH (2020) · cites this paper as [258]
FGF19 can act on CYP7A1, the rate-limiting enzyme in bile acid synthesis from cholesterol.
“FGF19 has the potential to regulate several pathways involved in NASH pathogenesis since it can act on CYP7A1, the rate limiting enzyme in BA synthesis from cholesterol, in addition to mimicking the effect of insulin on glycogen synthesis and gluconeogenesis [258].”
From Gut-pancreas-liver Axis as a target for treatment of NAFLD/NASH (2020) · cites this paper as [258]
Fibroblast growth factor 19 is an endocrine hormone induced in the gut by activation of the farnesoid X receptor.
“FGF19 is an endocrine hormone that is induced in the gut by activation of FXR.10”
From NGM282 for Treatment of Patients With Primary Biliary Cholangitis: A Multicenter, Randomized, Double‐Blind, Placebo‐Controlled Trial (2018) · cites this paper as [10]
FGF19 expression is induced in response to FXR activation in the ileum.
“FGF19 expression is induced in response to FXR activation in the ileum.10”
From NGM282 for Treatment of Patients With Primary Biliary Cholangitis: A Multicenter, Randomized, Double‐Blind, Placebo‐Controlled Trial (2018) · cites this paper as [10]
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- Authors
- Kliewer, S. A., & Mangelsdorf, D. J.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Howard Hughes Medical Institute (US)
- Venue
- Digestive Diseases
- Publisher
- S. Karger AG
- Published
- 2015
- Volume
- 33
- Issue
- 3
- Pages
- 327-331
- ISSN
- 0257-2753 (ISSN-L)
- 1421-9875
- PMC
- PMC4465534
- OpenAlex
- W1555526329
- Cited by
- 424
- References
- 51
- Citations by year
- 2026: 39 · 2025: 38 · 2024: 51 · 2023: 41 · 2022: 39 · 2021: 58 · 2020: 51 · 2019: 34 · 2018: 29 · 2017: 33 · 2016: 7 · 2015: 4
- FWCI
- 2.61
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Digestive Diseases (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-067158, R01DK067158)
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- bile acids, farnesoid X receptor, FGF15/19, bile acid signaling, enterohepatic circulation, postprandial metabolism, bile acid synthesis, gluconeogenesis, gallbladder filling, FXR agonists, primary biliary cirrhosis, bile acid diarrhea, metabolic disorders
- MeSH terms
- Receptor, Farnesoid X-Activated, Animals, Bile Acids and Salts, Cholesterol 7-alpha-Hydroxylase, Fibroblast Growth Factors, Gene Expression Regulation, Gluconeogenesis, Glycogen, Homeostasis, Humans, Insulin Resistance, Signal Transduction, Receptors, Cytoplasmic and Nuclear, Enterocytes, Lipid Metabolism, Mice
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