Paradoxical Regulation of Human FGF21 by Both Fasting and Feeding Signals: Is FGF21 a Nutritional Adaptation Factor?
Open accessAbstract
Fibroblast growth factor 21 (FGF21) has recently emerged as a metabolic hormone involved in regulating glucose and lipid metabolism in mouse, but the regulatory mechanisms and actions of FGF21 in humans remain unclear. Here we have investigated the regulatory mechanisms of the human FGF21 gene at the transcriptional level. A deletion study of the human FGF21 promoter (-1672 to +230 bp) revealed two fasting signals, including peroxisome proliferator-activated receptor α (PPARα) and glucagon signals, that independently induced human FGF21 gene transcription in mouse primary hepatocytes. In addition, two feeding signals, glucose and xylitol, also dose-dependently induced human FGF21 gene transcription and mRNA expression in both human HepG2 cells and mouse primary hepatocytes. FGF21 protein expression and secretion were also induced by high glucose stimulation. The human FGF21 promoter (-1672 to +230 bp) was found to have a carbohydrate-responsive element at -380 to -366 bp, which is distinct from the PPAR response element (PPRE). Knock-down of the carbohydrate response element binding protein by RNAi diminished glucose-induced human FGF21 transcription. Moreover, we found that a region from -555 to -443 bp of the human FGF21 promoter region exerts an important role in the activation of basic transcription. In conclusion, human FGF21 gene expression is paradoxically and independently regulated by both fasting and feeding signals. These regulatory mechanisms suggest that human FGF21 is increased with nutritional crisis, including starvation and overfeeding.
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Xylulose-5-phosphate activates ChREBP and promotes its binding to carbohydrate response element sites in promoters of target genes, including FGF21.
“An intermediate in this pathway, xylulose-5-phosphate, activates ChREBP (1) and promotes its binding to the carbohydrate response element sites in the promoters of target genes, including FGF21 (53, 130).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [130]
Stimulation of FGF21 production by carbohydrates is mediated by the transcription factor ChREBP.
“The stimulation of FGF21 production by carbohydrates is mediated by the transcription factor carbohydrate-response element-binding protein (ChREBP).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [130]
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- Authors
- Uebanso, T., Taketani, Y., Yamamoto, H., Amo, K., Ominami, H., Arai, H., Takei, Y., Masuda, M., Tanimura, A., Harada, N., Yamanaka-Okumura, H., & Takeda, E.
- Affiliations
- National Center for Global Health and Medicine (JP)
- Tokushima University (JP)
- Shizuoka University (JP)
- Corresponding author
- Taketani, Yutaka
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2011-08-01
- Volume
- 6
- Issue
- 8
- Pages
- e22976
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3148241
- OpenAlex
- W1999449586
- Cited by
- 99
- References
- 22
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 6 · 2023: 5 · 2022: 5 · 2021: 5 · 2020: 3 · 2019: 7 · 2018: 5 · 2017: 5 · 2016: 12 · 2015: 8 · 2014: 10 · 2013: 7 · 2012: 10
- FWCI
- 3.63
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (acceptedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- University of Tokushima
- Japan Society for the Promotion of Science (22680053, 19680030, 18300232, 18790567, 22890244, 22300237, 21300277)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Physiology › Dietary Effects on Health
- Keywords
- FGF21, transcriptional regulation, PPARα, glucagon, glucose, carp, hepatocytes, nutritional adaptation, lipid metabolism, glucose metabolism
- MeSH terms
- Animals, Cell Line, Fasting, Fibroblast Growth Factors, Gene Expression Regulation, Glucose, Humans, Male, Promoter Regions, Genetic, Xylitol, Signal Transduction, Polymerase Chain Reaction, Electrophoretic Mobility Shift Assay, Mice, Real-Time Polymerase Chain Reaction
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