A critical role for ChREBP-mediated FGF21 secretion in hepatic fructose metabolism
Open accessAbstract
OBJECTIVE: Increased fructose consumption is a contributor to the burgeoning epidemic of non-alcoholic fatty liver disease (NAFLD). Recent evidence indicates that the metabolic hormone FGF21 is regulated by fructose consumption in humans and rodents and may play a functional role in this nutritional context. Here, we sought to define the mechanism by which fructose ingestion regulates FGF21 and determine whether FGF21 contributes to an adaptive metabolic response to fructose consumption. METHODS: We tested the role of the transcription factor carbohydrate responsive-element binding protein (ChREBP) in fructose-mediated regulation of FGF21 using ChREBP knockout mice. Using FGF21 knockout mice, we investigated whether FGF21 has a metabolic function in the context of fructose consumption. Additionally, we tested whether a ChREBP-FGF21 interaction is likely conserved in human subjects. RESULTS: and its glycolytic, fructolytic, and lipogenic gene targets were attenuated in FGF21 knockout mice fed high-fructose diets, and this was accompanied by a 50% reduction in de novo lipogenesis a, 30% reduction VLDL secretion, and a 25% reduction in liver fat compared to fructose-fed controls. In human subjects, serum FGF21 correlates with de novo lipogenic rates measured by stable isotopic tracers (R = 0.55, P = 0.04) consistent with conservation of a ChREBP-FGF21 interaction. After 8 weeks of high-fructose diet, livers from FGF21 knockout mice demonstrate atrophy and fibrosis accompanied by molecular markers of inflammation and stellate cell activation; whereas, this did not occur in controls. CONCLUSIONS: In summary, ChREBP and FGF21 constitute a signaling axis likely conserved in humans that mediates an essential adaptive response to fructose ingestion that may participate in the pathogenesis of NAFLD and liver fibrosis.
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FGF21 is induced by simple-sugar intake in both mice and humans, and sugar-induced production of FGF21 from the liver occurs in a ChREBP-dependent manner.
“FGF21 is induced by simple-sugar intake in both mice and humans22,32,33, and that sugar-induced production of FGF21 from the liver occurs in a ChREBP-dependent manner22,121.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [121]
Mice lacking ChREBP fail to show an increase in plasma FGF21 levels in response to simple sugar intake.
“Mice lacking ChREBP fail to show an increase in plasma FGF21 levels in response to simple sugar intake (35, 133).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [35]
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 [142]
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 [142]
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 [142]
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 [142]
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ChREBP-Knockout Mice Show Sucrose Intolerance and Fructose Malabsorption
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Insulin Regulation of Hepatic Lipid Homeostasis
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- Authors
- Fisher, F. M., Kim, M., Doridot, L., Cunniff, J. C., Parker, T. S., Levine, D. M., Hellerstein, M. K., Hudgins, L. C., Maratos-Flier, E., & Herman, M. A.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Weill Cornell Medicine (US)
- University of California, Berkeley (US)
- Corresponding author
- Herman, Mark A.
- ORCID
- Venue
- Molecular Metabolism
- Publisher
- Elsevier BV
- Published
- 2017-01
- Volume
- 6
- Issue
- 1
- Pages
- 14-21
- ISSN
- 2212-8778 (ISSN-L)
- PMC
- PMC5220398
- OpenAlex
- W2556357555
- Cited by
- 166
- References
- 35
- Citations by year
- 2026: 10 · 2025: 16 · 2024: 13 · 2023: 12 · 2022: 20 · 2021: 21 · 2020: 18 · 2019: 23 · 2018: 12 · 2017: 21
- FWCI
- 9.70
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Metabolism (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- MAH (P30DK057521, R01DK100425)
- EMF (R01DK028082)
- General Clinical Research Center (M01-RR00102)
- Clinical Center for Translational Science award (UL1RR024143)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Keywords
- ChREBP, FGF21, fructose metabolism, non-alcoholic fatty liver disease, de novo lipogenesis, hepatic lipogenesis, VLDL secretion, liver fat, liver fibrosis, high-fructose diet, fructolysis, hepatic gene expression, FGF21 knockout mice, stable isotope tracers
- MeSH terms
- Animals, Female, Fibroblast Growth Factors, Fructose, Glycolysis, Humans, Liver, Male, Nuclear Proteins, Transcription Factors, Signal Transduction, Mice, Knockout, Hepatocytes, Lipogenesis, Mice, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Non-alcoholic Fatty Liver Disease
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