The DOI matches its Crossref record; 51 of the 51 references it cites were found in a registry or an index.
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 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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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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Citations
Cites
Identification of a nuclear receptor for bile acids
Makishima, M., Okamoto, A. Y., Repa, J. J., Tu, H., Learned, R. M., Luk, A., Hull, M. V., Lustig, K. D., Mangelsdorf, D. J., & Shan, B. (1999) · Science · doi:10.1126/science.284.5418.1362 · Cited by 2,714
Self-citationBile Acids: Natural Ligands for an Orphan Nuclear Receptor
Parks, D. J., Blanchard, S. G., Bledsoe, R. K., Chandra, G., Consler, T. G., Kliewer, S. A., Stimmel, J. B., Willson, T. M., Zavacki, A. M., Moore, D. D., et al. (1999) · Science · doi:10.1126/science.284.5418.1365 · Cited by 2,274
Self-citationA regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis
Goodwin, B., Jones, S. A., Price, R. R., Watson, M. A., McKee, D. D., Moore, L. B., Galardi, C., Wilson, J. G., Lewis, M. C., Roth, M. E., et al. (2000) · Molecular Cell · doi:10.1016/s1097-2765(00)00051-4 · Cited by 1,940
Self-citationFibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis
Inagaki, T., Choi, M., Moschetta, A., Peng, L., Cummins, C. L., McDonald, J. G., Luo, G., Jones, S. A., Goodwin, B., Richardson, J. A., et al. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.09.001 · Cited by 1,865
Self-citationTargeted Disruption of the Nuclear Receptor FXR/BAR Impairs Bile Acid and Lipid Homeostasis
Sinal, C. J., Tohkin, M., Miyata, M., Ward, J. M., Lambert, G., & Gonzalez, F. J. (2000) · Cell · doi:10.1016/s0092-8674(00)00062-3 · Cited by 1,819
Endogenous Bile Acids Are Ligands for the Nuclear Receptor FXR/BAR
Wang, H., Chen, J., Hollister, K., Sowers, L. C., & Forman, B. M. (1999) · Molecular Cell · doi:10.1016/s1097-2765(00)80348-2 · Cited by 1,636
A G Protein-coupled Receptor Responsive to Bile Acids
Kawamata, Y., Fujii, R., Hosoya, M., Harada, M., Yoshida, H., Miwa, M., Fukusumi, S., Habata, Y., Itoh, T., Shintani, Y., et al. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m209706200 · Cited by 1,628
Molecular Basis for Feedback Regulation of Bile Acid Synthesis by Nuclear Receptors
Lu, T. T., Makishima, M., Repa, J. J., Schoonjans, K., Kerr, T. A., Auwerx, J., & Mangelsdorf, D. J. (2000) · Molecular Cell · doi:10.1016/s1097-2765(00)00050-2 · Cited by 1,487
Self-citationBile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c
渡辺, 光., Houten, S. M., Wang, L., Moschetta, A., Mangelsdorf, D. J., Heyman, R. A., Moore, D. D., & Auwerx, J. H. (2004) · Journal of Clinical Investigation · doi:10.1172/jci21025 · Cited by 1,425
Self-citationIdentification of a nuclear receptor that is activated by farnesol metabolites
Forman, B. M., Goode, E., Chen, J., Oro, A. E., Bradley, D. J., Perlmann, T., Noonan, D. J., Burka, L. T., McMorris, T., Lamph, W. W., et al. (1995) · Cell · doi:10.1016/0092-8674(95)90530-8 · Cited by 1,210
Research works printed but not linked: 1
- 10.1210/en.143.5.1741 · DOI · Paper page
Cited by
Sorted by citations
Huang, F., Zheng, X., Ma, X., Jiang, R., Zhou, W., Zhou, S., Zhang, Y., Lei, S., Wang, S., Kuang, J., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-12896-x · Cited by 799
Nonalcoholic fatty liver disease as a nexus of metabolic and hepatic diseases
Samuel, V. T., & Shulman, G. I. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2017.08.002 · Cited by 745
“However, FXR also regulates the expression of numerous metabolic pathways, including gluconeogenesis and lipogenesis (Kliewer and Mangelsdorf, 2015).”
The gut–liver axis and gut microbiota in health and liver disease
Hsu, C. L., & Schnabl, B. (2023) · Nature Reviews Microbiology · doi:10.1038/s41579-023-00904-3 · Cited by 737
Diversification of host bile acids by members of the gut microbiota
Winston, J. A., & Theriot, C. M. (2019) · Gut Microbes · doi:10.1080/19490976.2019.1674124 · Cited by 597
Bile acid metabolism and signaling, the microbiota, and metabolic disease
Cai, J., Rimal, B., Jiang, C., Chiang, J. Y. L., & Patterson, A. D. (2022) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2022.108238 · Cited by 529
Metadata
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › 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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