Tissue-specific Expression of βKlotho and Fibroblast Growth Factor (FGF) Receptor Isoforms Determines Metabolic Activity of FGF19 and FGF21
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The fibroblast growth factor (FGF) 19 subfamily of ligands, FGF19, FGF21, and FGF23, function as hormones that regulate bile acid, fatty acid, glucose, and phosphate metabolism in target organs through activating FGF receptors (FGFR1-4). We demonstrated that Klotho and betaKlotho, homologous single-pass transmembrane proteins that bind to FGFRs, are required for metabolic activity of FGF23 and FGF21, respectively. Here we show that, like FGF21, FGF19 also requires betaKlotho. Both FGF19 and FGF21 can signal through FGFR1-3 bound by betaKlotho and increase glucose uptake in adipocytes expressing FGFR1. Additionally, both FGF19 and FGF21 bind to the betaKlotho-FGFR4 complex; however, only FGF19 signals efficiently through FGFR4. Accordingly, FGF19, but not FGF21, activates FGF signaling in hepatocytes that primarily express FGFR4 and reduces transcription of CYP7A1 that encodes the rate-limiting enzyme for bile acid synthesis. We conclude that the expression of betaKlotho, in combination with particular FGFR isoforms, determines the tissue-specific metabolic activities of FGF19 and FGF21.
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Loss of KLB abolishes all effects of FGF21 in vitro and in vivo.
“loss of KLB abolishes all effects of FGF21 in vitro and in vivo46,53–56.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [46]
FGF21 binding promotes formation of a dimeric FGFR1c-KLB complex, activates tyrosine kinase domains and propagates signalling through ERK phosphorylation.
“FGF21 binding promotes the formation of a dimeric FGFR1c–KLB signalling complex, which activates the intracellular tyrosine kinase domains of FGFR1c and propagates signalling through phosphorylation by the kinase ERK46,53,58,59”
From Metabolic messengers: FGF21 (2021) · cites this paper as [46]
FGF21 signals by binding and activating a receptor complex composed of KLB and FGFR1c.
“FGF21 elicits its biological effects by binding and activating a receptor complex composed of the co-receptor KLB and a traditional FGF receptor, fibroblast growth factor receptor 1c (FGFR1c)46,47.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [46]
Both FGF21 and another endocrine FGF, FGF15/19, share a requirement for KLB for signaling.
“Interestingly, both FGF21 and another endocrine FGF, FGF15/19, share a requirement for KLB for signaling46,54, but what cross-talk, if any, exists between these signalling pathways in both physiological and pharmacological settings is unclear.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [46]
FGF21 signals to a receptor complex comprised of FGFR1c and KLB.
“FGF21 signals to a receptor complex comprised of FGF receptor 1c (FGFR1c) and its co-receptor β-klotho (KLB) [[143], [144], [145], [146]].”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [143]
Endocrine FGFs require a coreceptor to provide signaling specificity, which for FGF21 and FGF19 is β-klotho.
“Importantly, since FGF receptors are ubiquitously expressed, endocrine FGFs require a coreceptor to provide signaling specificity, which for FGF21 and FGF19 is the coreceptor β-klotho (71, 99, 140).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [71]
FGF21 functions in target tissues that express FGFR1c and the obligate coreceptor β-klotho.
“FGF21 functions in target tissues that express the traditional FGF receptor FGFR1c and the obligate coreceptor β-klotho (2, 27, 71, 99, 124, 140).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [71]
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- Authors
- Kurosu, H., Choi, M., Ogawa, Y., Dickson, A. S., Goetz, R., Eliseenkova, A. V., Mohammadi, M., Rosenblatt, K. P., Kliewer, S. A., & Kuro-o, M.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- New York University (US)
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2007-09
- Volume
- 282
- Issue
- 37
- Pages
- 26687-26695
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2496965
- OpenAlex
- W2048411348
- Cited by
- 748
- References
- 35
- Citations by year
- 2026: 37 · 2025: 24 · 2024: 33 · 2023: 31 · 2022: 55 · 2021: 46 · 2020: 44 · 2019: 48 · 2018: 52 · 2017: 47 · 2016: 38 · 2015: 40 · 2014: 43 · 2013: 43 · 2012: 51
- FWCI
- 10.87
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Ellison Medical Foundation
- Welch Foundation
- Ted Nash Long Life Foundation
- Eisai
- National Institutes of Health (1r01ag015326-01, DK067158)
- National Institute on Aging (R01AG19712, R01AG025326, R01 AG 15326, R01AG019712)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-067158, R01DK067158)
- National Institute of Dental and Craniofacial Research (R01DE13686, R01DE013686)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Nephrology › Parathyroid Disorders and Treatments
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- β-Klotho, Klotho, FGF19, FGF21, fibroblast growth factor 23, fibroblast growth factor receptor, FGFR4, FGFR1, tissue-specific signaling, bile acid metabolism, CYP7A1, hepatocytes, metabolic hormones
- MeSH terms
- Fibroblast Growth Factor-23, Klotho Proteins, Animals, Cholesterol 7-alpha-Hydroxylase, Fibroblast Growth Factors, Humans, Membrane Proteins, Organ Specificity, Phosphorylation, Signal Transduction, Adipocytes, Protein Isoforms, Hepatocytes, 3T3-L1 Cells, Extracellular Signal-Regulated MAP Kinases, Mice, Rats, ErbB Receptors
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