Fibroblast growth factor 21 (FGF21) is robustly induced by ethanol and has a protective role in ethanol associated liver injury
Open accessAbstract
OBJECTIVE: Excess ethanol consumption has serious pathologic consequences. In humans, repeated episodes of binge drinking can lead to liver damage and have adverse effects on other organs such as pancreas and brain. Long term chronic consumption of ethanol can also result in progressive alcoholic liver disease and cirrhosis. Fibroblast growth factor 21 (FGF21) is a metabolic regulator with multiple physiologic functions. FGF21 is a novel biomarker for non-alcoholic fatty liver disease (NAFLD) in humans and limits hepatotoxicity in mice. Therefore, we explored the possibility that FGF21 plays a role in response to ethanol consumption in both humans and mice. METHODS: We used a binge drinking paradigm in humans to examine the effect of acute ethanol consumption on circulating FGF21. We adapted this paradigm to evaluate the acute response to ethanol in mice. We then examined the role of FGF21 on liver pathology in two models of chronic ethanol consumption in both wild type (WT) mice and mice lacking FGF21 (FGF21-KO). RESULTS: Acute ethanol consumption resulted in a robust induction of serum FGF21 after 6 h in both humans and mice. Serum ethanol peaked at 1 h in both species and was cleared by 6 h. Ethanol clearance was the same in WT and FGF21-KO mice, indicating that FGF21 does not play a major role in ethanol metabolism in a binge paradigm. When FGF21-KO mice were fed the Lieber-DeCarli diet, a high fat diet supplemented with ethanol, a higher mortality was observed compared to WT mice after 16 days on the diet. When FGF21-KO mice consumed 30% ethanol in drinking water, along with a normal chow diet, there was no mortality observed even after 16 weeks, but the FGF21-KO mice had significant liver pathology compared to WT mice. CONCLUSIONS: Acute or binge ethanol consumption significantly increases circulating FGF21 levels in both humans and mice. However, FGF21 does not play a role in acute ethanol clearance. In contrast, chronic ethanol consumption in the absence of FGF21 is associated with significant liver pathology alone or in combination with excess mortality, depending on the type of diet consumed with ethanol. This suggests that FGF21 protects against long term ethanol induced hepatic damage and may attenuate progression of alcoholic liver disease. Further study is required to assess the therapeutic potential of FGF21 in the treatment of alcoholic liver disease.
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FGF21 production by the liver is increased in response to alcohol intake.
“Similarly to its regulation of nutrient homeostasis, FGF21 production by the liver is also increased in response to alcohol intake132,133, and administration of FGF21 suppresses alcohol intake122,134.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [132]
Hepatic FGF21 increases in response to nutritional stimuli including macronutrient imbalance and alcohol intake.
“several recent studies confirmed that hepatic FGF21 increases in response to other nutritional stimuli, including conditions of macronutrient imbalance [152], and in response to alcohol intake [138,140,153].”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [153]
FGF21 protects against alcohol-induced liver injury.
“and FGF21 protects against alcohol-induced liver injury.”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [26]
Mice lacking FGF21 develop marked liver steatosis and injury in response to chronic alcohol consumption despite being able to clear ethanol as effectively as wild-type controls.
“Mice that lack FGF21 develop marked liver steatosis and injury in response to chronic alcohol consumption despite being able to clear ethanol as effectively as wild-type controls (26).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [26]
Alcohol consumption robustly increases FGF21, largely by the liver.
“another nutritional intervention was shown to robustly increase FGF21: alcohol consumption. Ample evidence, in both rodents and humans, demonstrates that ethanol intake increases FGF21 production, largely by the liver”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [164]
The core effect of FGF21 to suppress sweet and alcohol intake has been replicated by additional studies.
“this core effect of FGF21 to suppress sweet and alcohol intake has since been replicated by additional studies”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [164]
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- Authors
- Desai, B. N., Singhal, G., Watanabe, M., Stevanovic, D., Lundasen, T., Fisher, F. M., Mather, M. L., Vardeh, H. G., Douris, N., Adams, A. C., Nasser, I. A., FitzGerald, G. A., Flier, J. S., Skarke, C., & Maratos-Flier, E.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Eli Lilly (United States) (US)
- University of Pennsylvania (US)
- ORCID
- Venue
- Molecular Metabolism
- Publisher
- Elsevier BV
- Published
- 2017-11
- Volume
- 6
- Issue
- 11
- Pages
- 1395-1406
- ISSN
- 2212-8778 (ISSN-L)
- PMC
- PMC5681240
- OpenAlex
- W2749688538
- Cited by
- 150
- References
- 43
- Citations by year
- 2026: 12 · 2025: 20 · 2024: 17 · 2023: 16 · 2022: 19 · 2021: 21 · 2020: 17 · 2019: 15 · 2018: 12
- FWCI
- 4.92
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Molecular Metabolism (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- 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)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Funders
- American Heart Association
- JPB Foundation
- National Institutes of Health (UL1TR000003, DK028082, DK034854, ES013508)
- Harvard Digestive Diseases Center, Harvard University (P30DK034854, DK034854)
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK P30, DK034854, DK028082, R01DK028082, P30DK034854)
- National Institute of Environmental Health Sciences (ES013508-05, ES013508, P30ES013508)
- National Center for Research Resources (UL1RR024134)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- FGF21, ethanol, binge drinking, alcoholic liver disease, ethanol-induced liver injury, hepatoprotection, FGF21 knockout mice, ethanol clearance, mortality, biomarkers, chronic alcohol consumption, Lieber-DeCarli diet, alcohol metabolism, liver pathology
- MeSH terms
- Adult, Ethanol, Animals, Fatty Liver, Alcoholic, Female, Fibroblast Growth Factors, Humans, Liver, Liver Cirrhosis, Liver Diseases, Alcoholic, Longitudinal Studies, Male, Mice, Inbred C57BL, Random Allocation, Mice, Knockout, Mice
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