A Specific ChREBP and PPARα Cross-Talk Is Required for the Glucose-Mediated FGF21 Response
Open accessAbstract
While the physiological benefits of the fibroblast growth factor 21 (FGF21) hepatokine are documented in response to fasting, little information is available on Fgf21 regulation in a glucose-overload context. We report that peroxisome-proliferator-activated receptor α (PPARα), a nuclear receptor of the fasting response, is required with the carbohydrate-sensitive transcription factor carbohydrate-responsive element-binding protein (ChREBP) to balance FGF21 glucose response. Microarray analysis indicated that only a few hepatic genes respond to fasting and glucose similarly to Fgf21 . Glucose-challenged Chrebp −/− mice exhibit a marked reduction in FGF21 production, a decrease that was rescued by re-expression of an active ChREBP isoform in the liver of Chrebp −/− mice. Unexpectedly, carbohydrate challenge of hepatic Ppar α knockout mice also demonstrated a PPARα-dependent glucose response for Fgf21 that was associated with an increased sucrose preference. This blunted response was due to decreased Fgf21 promoter accessibility and diminished ChREBP binding onto Fgf21 carbohydrate-responsive element (ChoRE) in hepatocytes lacking PPARα. Our study reports that PPARα is required for the ChREBP-induced glucose response of FGF21.
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Hepatic mRNA and plasma protein levels of FGF21 are induced by high sugar intake through a ChREBP-dependent mechanism.
“Hepatic mRNA and plasma protein levels of FGF21 are induced by high sugar intake through a mechanism dependent on the transcription factor ChREBP22–25”
From Metabolic messengers: FGF21 (2021) · cites this paper as [25]
Circulating FGF21 levels are robustly increased by diets that are high in carbohydrate but low in protein.
“Circulating FGF21 levels are robustly increased by diets that are high in carbohydrate but low in protein”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [140]
The carbohydrate-driven increase in FGF21 is driven at least in part by ChREBP, which binds directly to the FGF21 promoter.
“driven at least in part by the transcription factor carbohydrate response element binding protein (ChREBP), which binds directly to the FGF21 promoter”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [140]
Liver FGF21 production is robustly stimulated by an imbalance in macronutrients, particularly settings of high-carbohydrate but low-protein intake.
“liver FGF21 production seems to be robustly stimulated by an imbalance in macronutrients, particularly settings of high-carbohydrate but low-protein intake”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [140]
Both acute carbohydrate ingestion and long-term exposure to high-carbohydrate diets significantly increase liver FGF21 mRNA expression and circulating FGF21 levels.
“Both acute carbohydrate ingestion and long-term exposure to high-carbohydrate diets significantly increase liver FGF21 mRNA expression and circulating FGF21 levels”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [140]
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Self-citation
- Authors
- Iroz, A., Montagner, A., Benhamed, F., Levavasseur, F., Polizzi, A., Anthony, E., Régnier, M., Fouché, E., Lukowicz, C., Cauzac, M., Tournier, E., Do-Cruzeiro, M., Daujat-Chavanieu, M., Gerbal-Chalouin, S., Fauveau, V., Marmier, S., Burnol, A.-F., Guilmeau, S., Lippi, Y., Girard, J., Wahli, W., Dentin, R., Guillou, H., & Postic, C.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Université Toulouse III - Paul Sabatier (FR)
- Corresponding author
- Dentin, Renaud
- Guillou, Hervé
- Postic, Catherine
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2017-10
- Volume
- 21
- Issue
- 2
- Pages
- 403-416
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC5643524
- OpenAlex
- W2762631272
- Cited by
- 128
- References
- 49
- Citations by year
- 2026: 2 · 2025: 11 · 2024: 13 · 2023: 14 · 2022: 23 · 2021: 19 · 2020: 18 · 2019: 14 · 2018: 12 · 2017: 2
- FWCI
- 5.14
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- SERVAL (Université de Lausanne) (publishedVersion, other-oa)
- HAL (submittedVersion, cc-by-nc-nd)
- IRIS (submittedVersion, cc-by-nc-nd)
- HAL (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DR-NTU (Nanyang Technological University) (submittedVersion, cc-by-nc-nd)
- Funders
- Fondation pour la Recherche Médicale (DEQ20150331744)
- Lee Kong Chian School of Medicine, Nanyang Technological University
- Florey Medical Research Foundation
- HORIZON EUROPE Marie Sklodowska-Curie Actions (H2020-MSCA-ITN-2015-675610)
- European Foundation for the Study of Diabetes
- European Research Council (ERC-2013-StG-336629)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- FGF21, ChREBP, PPARα, glycemic response, fasting response, hepatic gene regulation, sucrose preference, PPARα knockout mice, hepatocytes
- MeSH terms
- Animals, Cells, Cultured, Female, Fibroblast Growth Factors, Glucose, Male, Mice, Inbred C57BL, Nuclear Proteins, Transcription Factors, Response Elements, Hepatocytes, PPAR alpha, Mice, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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